Convergent mechanisms for dysregulation of mitochondrial quality control in metabolic disease: implications for mitochondrial therapeutics.
Mitochondrial dysfunction is associated with a broad range of pathologies including diabetes, ethanol toxicity, metabolic syndrome and cardiac failure. It is now becoming clear that maintaining mitochondrial quality through a balance between biogenesis, reserve capacity and mitophagy is critical in determining the response to metabolic or xenobiotic stress. In diseases associated with metabolic stress, such as Type II diabetes and non-alcoholic and alcoholic steatosis, the mitochondria are subjected to multiple 'hits' such as hypoxia and oxidative and nitrative stress, which can overwhelm the mitochondrial quality control pathways. In addition, the underlying mitochondrial genetics that evolved to accommodate high-energy demand, low-calorie supply environments may now be maladapted to modern lifestyles (low-energy demand, high-calorie environments). The pro-oxidant and pro-inflammatory environment of a sedentary western lifestyle has been associated with modified redox cell signalling pathways such as steatosis, hypoxic signalling, inflammation and fibrosis. These data suggest that loss of mitochondrial quality control is intimately associated with the aberrant activation of redox cell signalling pathways under pathological conditions. In the present short review, we discuss evidence from alcoholic liver disease supporting this concept, the insights obtained from experimental models and the application of bioenergetic-based therapeutics in the context of maintaining mitochondrial quality.
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Tanecia
T
Mitchell
Balu
B
Chacko
Scott W
SW
Ballinger
Shannon M
SM
Bailey
Jianhua
J
Zhang
Victor
V
Darley-Usmar
D006801:Humans; D008659:Metabolic Diseases / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress; D057285:Precision Medicine; D011786:Quality Control; D015398:Signal Transduction