scholarly journals Inhibiting mitochondrial Complex I or Complex III differentially affects mitochondrial physiology

2012 ◽  
Vol 1817 ◽  
pp. S55
Author(s):  
M. Forkink ◽  
R. Brock ◽  
J.Smeitink ◽  
P. Willems ◽  
W. Koopman
Keyword(s):  
Complex I ◽  
Complex Iii ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex

scholarly journals Adverse effects of anti-tuberculosis drugs on HepG2 cell bioenergetics

2016 ◽  
Vol 36 (6) ◽  
pp. 616-625 ◽  
Author(s):  
E Elmorsy ◽  
SM Attalla ◽  
E Fikry ◽  
A Kocon ◽  
R Turner ◽  
...  
Keyword(s):  
Complex I ◽  
Drug Exposure ◽  
Lactate Production ◽  
Complex Iii ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Drug Induced ◽  
Atp Levels ◽  
Drug Treatments ◽  
Complex I Activity

Tuberculosis (TB) is an intractable chronic infection. Disease treatment with anti-TB drugs remains challenging due to drug-induced hepatotoxicity. The toxicity of the anti-TB drugs rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) either alone or in combination was investigated in HepG2 cells. Assays of intracellular adenosine triphosphate (ATP) levels at 4-, 24- and 48-h post-exposure to gradient concentrations of RIF, INH and PZA were conducted. Drug-induced effects on mitochondrial membrane potential (MMP), mitochondrial complex I and complex III activity, nicotinamide adenine dinucleotide (NAD+) levels and cellular lactate production were assessed. Decreased ATP levels were dose-dependent and correlated with drug exposure duration. Approximate 24-h IC50s were 0.5 mM, 70 mM and 84 mM for RIF, INH and PZA, respectively. Twenty-four hours post-drug treatment, reductions of MMP ( p = 0.0005), mitochondrial complex I and III activities ( p = 0.0001 and p = 0.0003, respectively), NAD+ levels ( p = 0.0057) and increased lactate production ( p < 0.0001) were observed. Drug combinations used to mimic cumulative drug treatments induced a synergistic inhibition of mitochondrial complex I activity. An assessment of cellular ultrastructure using transmission electron microscopy indicated drug-induced mitophagy. Collectively, our study suggests that hepatotoxicity of commonly employed anti-TB drugs is mediated by their curtailment of mitochondrial function.

scholarly journals Metabolic determinants of cellular fitness dependent on mitochondrial reactive oxygen species

2020 ◽  
Vol 6 (45) ◽  
pp. eabb7272
Author(s):  
Hyewon Kong ◽  
Colleen R. Reczek ◽  
Gregory S. McElroy ◽  
Elizabeth M. Steinert ◽  
Tim Wang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cancer Cells ◽  
Complex I ◽  
Lymphoblastic Leukemia ◽  
Reactive Oxygen ◽  
Complex Iii ◽  
Mitochondrial Complex I ◽  
Oxygen Species ◽  
Mitochondrial Complex

Mitochondria-derived reactive oxygen species (mROS) are required for the survival, proliferation, and metastasis of cancer cells. The mechanism by which mitochondrial metabolism regulates mROS levels to support cancer cells is not fully understood. To address this, we conducted a metabolism-focused CRISPR-Cas9 genetic screen and uncovered that loss of genes encoding subunits of mitochondrial complex I was deleterious in the presence of the mitochondria-targeted antioxidant mito-vitamin E (MVE). Genetic or pharmacologic inhibition of mitochondrial complex I in combination with the mitochondria-targeted antioxidants, MVE or MitoTEMPO, induced a robust integrated stress response (ISR) and markedly diminished cell survival and proliferation in vitro. This was not observed following inhibition of mitochondrial complex III. Administration of MitoTEMPO in combination with the mitochondrial complex I inhibitor phenformin decreased the leukemic burden in a mouse model of T cell acute lymphoblastic leukemia. Thus, mitochondrial complex I is a dominant metabolic determinant of mROS-dependent cellular fitness.

scholarly journals Assembly of the mitochondrial Complex I assembly complex suggests a regulatory role for deflavination

2020 ◽  
Author(s):  
Gabriele Giachin ◽  
Matthew Jessop ◽  
Romain Bouverot ◽  
Samira Acajjaoui ◽  
Melissa Saidi ◽  
...  
Keyword(s):  
Complex I ◽  
Regulatory Role ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Complex I Assembly
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