New inhibitors of Complex I of the mitochondrial electron transport chain with activity as pesticides

1994 ◽  
Vol 22 (1) ◽  
pp. 230-233 ◽  
Author(s):  
Robert M. Hollingworth ◽  
Kabeer I. Ahammadsahib ◽  
G. Gadelhak ◽  
J. L. McLaughlin
Keyword(s):  
Electron Transport ◽  
Complex I ◽  
Electron Transport Chain ◽  
Mitochondrial Electron Transport Chain ◽  
Transport Chain

scholarly journals Targeting the complex I and III of mitochondrial electron transport chain as a potentially viable option in liver cancer management

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Qin Yang ◽  
Ling Wang ◽  
Jiaye Liu ◽  
Wanlu Cao ◽  
Qiuwei Pan ◽  
...  
Keyword(s):  
Electron Transport ◽  
Liver Cancer ◽  
Therapeutic Target ◽  
Complex I ◽  
Electron Transport Chain ◽  
Metabolic Reprogramming ◽  
Complex Iii ◽  
Mitochondrial Electron Transport Chain ◽  
Potential Therapeutic Target ◽  
Transport Chain

AbstractLiver cancer is one of the most common and lethal types of oncological disease in the world, with limited treatment options. New treatment modalities are desperately needed, but their development is hampered by a lack of insight into the underlying molecular mechanisms of disease. It is clear that metabolic reprogramming in mitochondrial function is intimately linked to the liver cancer process, prompting the possibility to explore mitochondrial biochemistry as a potential therapeutic target. Here we report that depletion of mitochondrial DNA, pharmacologic inhibition of mitochondrial electron transport chain (mETC) complex I/complex III, or genetic of mETC complex I restricts cancer cell growth and clonogenicity in various preclinical models of liver cancer, including cell lines, mouse liver organoids, and murine xenografts. The restriction is linked to the production of reactive oxygen species, apoptosis induction and reduced ATP generation. As a result, our findings suggest that the mETC compartment of mitochondria could be a potential therapeutic target in liver cancer.

scholarly journals Differential requirements for mitochondrial electron transport chain components in the adult murine liver

2021 ◽  
Author(s):  
Nicholas P Lesner ◽  
Xun Wang ◽  
Anderson Frank ◽  
Sara House ◽  
Spencer D Shelton ◽  
...  
Keyword(s):  
Electron Transport ◽  
Liver Function ◽  
Liver Damage ◽  
Complex I ◽  
Electron Transport Chain ◽  
Mouse Liver ◽  
Alternative Pathway ◽  
Redox Status ◽  
Mitochondrial Electron Transport Chain ◽  
Transport Chain

Mitochondrial electron transport chain (ETC) dysfunction is a common cause of metabolic disease in humans, but the mechanisms underlying tissue specific phenotypes are not understood. Complex I (cI) is classically considered the entry point for electrons into the ETC, and in vitro experiments indicate that cI is required for maintenance of the NAD+/NADH ratio, an indicator of cellular redox status. This finding has largely not been tested in vivo. Here, we report that mitochondrial complex I (cI) is dispensable for homeostasis of the adult mouse liver; animals with hepatocyte-specific loss of cI function display no overt phenotypes or signs of liver damage, and maintain liver function and redox status. Further analysis of cI-deficient livers did not reveal significant proteomic or metabolic changes, indicating little to no compensation is required in the setting of complex I loss. In contrast, complex IV (cIV) dysfunction in adult hepatocytes results in decreased liver function, steatosis, and liver damage, accompanied by significant metabolomic and proteomic perturbations. Correspondingly, we find that complex I-deficient livers are reliant on an alternative pathway, whereby electrons are donated to the ETC via dihydroorotate dehydrogenase, to maintain redox status. Our results support a model whereby complex I loss is tolerated in the mouse liver because hepatocytes make use of alternative electron donors to fuel the mitochondrial ETC.

Sign in / Sign up

Export Citation Format

Share Document