Advertisement

ResearchIn-Press PreviewCell biologyHepatologyMetabolism Open Access | 10.1172/JCI204023

Excessive EFHD1-dependent ER-mitochondrial contacts drive a maladaptive antiviral response in metabolic liver disease

David R. Eberhardt,1 Emma C. Rekate,1 Yasmin B. Masini,1 Hannah E. Duron,1 David Mollinedo,1 Adrian M. Velarde,1 Devorah Stucki,2 Tara R. Price,2 Sandra H.J. Lee,1 Enrique Balderas,1 Neeraj K. Rai,1 Ashley R. Bratt,1 Anthony M. Balynas,1 Chris J. Stubben,3 Ryan Bia,1 Sudipa Maity,4 Nicolas Hartel,4 Xue Yin,1 Andrea Corbin,1 Anshu Kumari,5 Dung M. Nguyen,5 Daisuke Shimura,1 Vu D. Nguyen,1 Vishaka Vinod,6 Kamrul H. Chowdhury,6 Francisco Verdeguer,7 Joel Zvick,7 Patrice N. Mimche,8 Sihem Boudina,6 Stavros G. Drakos,1 Ademuyiwa S. Aromolaran,1 Sarah Franklin,1 Vivek Garg,5 Robin M. Shaw,1 William L. Holland,6 Scott A. Summers,6 Marcus G. Pezzolesi,2 Jared Rutter,9 Kimberley J. Evason,10 and Dipayan Chaudhuri1

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Eberhardt, D. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Rekate, E. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Masini, Y. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Duron, H. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Mollinedo, D. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Velarde, A. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Stucki, D. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Price, T. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Lee, S. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Balderas, E. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Rai, N. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Bratt, A. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Balynas, A. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Stubben, C. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Bia, R. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Maity, S. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Hartel, N. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Yin, X. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Corbin, A. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Kumari, A. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Nguyen, D. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Shimura, D. in: PubMed | Google Scholar |

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Nguyen, V. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Vinod, V. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Chowdhury, K. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Verdeguer, F. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Zvick, J. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Mimche, P. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Boudina, S. in: PubMed | Google Scholar |

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Drakos, S. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Aromolaran, A. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Franklin, S. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Garg, V. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Shaw, R. in: PubMed | Google Scholar |

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Holland, W. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Summers, S. in: PubMed | Google Scholar |

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Pezzolesi, M. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Rutter, J. in: PubMed | Google Scholar |

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Evason, K. in: PubMed | Google Scholar

1Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States of America

2Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, United States of America

3Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

4Thermo Fisher Scientific, San Jose, United States of America

5Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, United States of America

6Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States of America

7InSphero AG, Schlieren, United States of America

8Department of Dermatology, Indiana University School of Medicine, Indianapolis, United States of America

9Howard Hughes Medical Institute, Department of Biochemistry, University of Utah, Salt Lake City, United States of America

10Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States of America

Find articles by Chaudhuri, D. in: PubMed | Google Scholar

Published September 1, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI204023.
Copyright © 2026, Eberhardt et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 1, 2026 - Version history
View PDF
Abstract

Metabolic-associated steatohepatitis (MASH) involves hepatocyte damage that cannot be explained solely by lipid accumulation. Here, to discover injury-specific pathways, we focused on a gene of uncertain function, EF-Hand Domain Family Member D1 (EFHD1), identified in human genome-wide association studies of liver injury but not liver fat. We show that EFHD1, a Ca2+-dependent actin crosslinker, stabilizes endoplasmic reticulum–mitochondria contact sites (ERMCS), detecting spatiotemporal coincidence of inter-organellar proximity and ER Ca2+ release. During MASH, EFHD1 upregulation drives pathological mitochondrial fragmentation via excessive contact persistence. This structural failure promotes mitochondrial double-stranded RNA escape and activation of a maladaptive antiviral PKR-associated stress response, a causal relationship also supported by Mendelian randomization in humans. Consequently, inhibiting EFHD1 in human and mouse models blunts hepatocyte damage. These findings identify EFHD1 as a Ca2+-dependent ERMCS stabilizer, reveal a hepatocyte-intrinsic injury pathway, and suggest EFHD1 inhibition as a therapeutic strategy.

Graphical Abstract
graphical abstract
Supplemental material

View Unedited blot and gel images

View

View Supplemental Tables S1-S11

Version history
  • Version 1 (September 1, 2026): In-Press Preview
Advertisement
Advertisement