Mitochondrial complex I activity modulates tumor growth and metastasis.
(A) Ndi1 expression inhibited mammary fat pad tumor growth of MDA-MB-435 and MDA-MB-231 cells. Control cells were transduced with empty vector (n = 6). (B) Ndi1 expression inhibited lung colonization (experimental metastasis) by MDA-MB-435 or MDA-MB-231 cells after i.v. injection. Control cells were transduced with empty vector (n = 6). (C) Ndi1 expression inhibited multiorgan experimental metastasis, as indicated by noninvasive bioluminescence imaging 7 weeks after i.v. injection of 2.5 × 105 MDA-MB-435 control or Ndi1-expressing cells (n = 5). (D) Knockdown of complex I subunit NFUFV1 expression inhibited complex I activity and respiratory capacity in MDA-MB-435 cells. NDUFV1-knockdown (shV1) and control (shCT) cells were compared. Complex I was immunocaptured from cell lysates, analyzed based on oxidation of NADH to NAD+, expressed as mean OD/min/mg protein (n = 3). Routine mitochondrial respiration, corrected for residual oxygen consumption due to oxidative side reactions, was measured in intact MDA-MB-435 control and NDUFV1-knockdown cells by high-resolution respirometry (n = 3). (E) NDUFV1 knockdown increased lung colonization activity in MDA-MB-435 cells. NDUFV1-knockdown and control cells were compared (n = 8). Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, nonparametric Mann-Whitney test (A, B, and E) or unpaired 2-tailed Student’s t test (D).