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Altered mitochondrial function in insulin-deficient and insulin-resistant states
Gregory N. Ruegsegger, … , Surendra Dasari, K. Sreekumaran Nair
Gregory N. Ruegsegger, … , Surendra Dasari, K. Sreekumaran Nair
Published August 31, 2018
Citation Information: J Clin Invest. 2018;128(9):3671-3681. https://doi.org/10.1172/JCI120843.
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Review Series

Altered mitochondrial function in insulin-deficient and insulin-resistant states

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Abstract

Diabetes profoundly alters fuel metabolism; both insulin deficiency and insulin resistance are characterized by inefficient mitochondrial coupling and excessive production of reactive oxygen species (ROS) despite their association with normal to high oxygen consumption. Altered mitochondrial function in diabetes can be traced to insulin’s pivotal role in maintaining mitochondrial proteome abundance and quality by enhancing mitochondrial biogenesis and preventing proteome damage and degradation, respectively. Although insulin enhances gene transcription, it also induces decreases in amino acids. Thus, if amino acid depletion is not corrected, increased transcription will not result in enhanced translation of transcripts to proteins. Mitochondrial biology varies among tissues, and although most studies in humans are performed in skeletal muscle, abnormalities have been reported in multiple organs in preclinical models of diabetes. Nutrient excess, especially fat excess, alters mitochondrial physiology by driving excess ROS emission that impairs insulin action. Excessive ROS irreversibly damages DNA and proteome with adverse effects on cellular functions. In insulin-resistant people, aerobic exercise stimulates both mitochondrial biogenesis and efficiency concurrent with enhancement of insulin action. This Review discusses the association between both insulin-deficient and insulin-resistant diabetes and alterations in mitochondrial proteome homeostasis and function that adversely affect cellular functions, likely contributing to many diabetic complications.

Authors

Gregory N. Ruegsegger, Ana L. Creo, Tiffany M. Cortes, Surendra Dasari, K. Sreekumaran Nair

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Figure 1

The mitochondrial proteome in the presence and absence of insulin signaling.

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The mitochondrial proteome in the presence and absence of insulin signal...
(A) Insulin binding to the insulin receptor (IR) initiates a downstream signaling cascade leading to the phosphorylation of insulin receptor substrates (IRS1/2) and activation of AKT, the major node of insulin signaling. Of the many downstream effectors of AKT, the inhibition of FOXO1 influences the expression and activity of PPARγ coactivator 1α (PGC1A), which activates transcription factors (e.g., myocyte enhancer factor 2 [MEF2], nuclear respiratory factor 1 [NRF1], NRF2) that control nuclear-encoded mitochondrial gene expression. PGC1A also enhances the transcription of mitochondrial genes through transcription factor A, mitochondrial (TFAM). In the presence of appropriate amino acid concentrations, activation of mTOR and its downstream targets increases the synthesis of nuclear-encoded mitochondrial proteins in the cytoplasm, which are imported into the mitochondria to form TCA cycle, β-oxidation, and ETC complex proteins. Mitochondrial-encoded genes are synthesized in the mitochondria and form ETC complex proteins. Collectively, these increase the mitochondrial proteome and ATP production. (B) Insulin deficiency decreases the transcription of nuclear-encoded and mitochondrial-encoded mitochondrial genes and the synthesis of mitochondrial proteins, and increases oxidative stress and gene expression central to the proteasome pathway (e.g., the E3 ubiquitin ligase TRIM63) and autophagy pathway (e.g., Beclin), leading to increased degradation of mitochondrial proteins. Collectively, these responses decrease the mitochondrial proteome and ATP production. Additional abbreviations: 4EBP1, eukaryotic translation initiation factor 4E–binding protein 1; p70S6K, 70-kDa ribosomal S6 kinase.
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