Convergent mechanisms for dysregulation of mitochondrial quality control in metabolic disease: implications for mitochondrial therapeutics

Abstract

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.

Figure 1. Mitochondrial Quality Control is Regulated by Mitochondrial Biogenesis and Mitophagy

It is well known that during alcoholic liver disease cytochrome P450 (CYP2E1) and inducible nitric oxide synthase (iNOS) are upregulated and this leads to aldehyde (R-CHO) and peroxynitrite (ONOO⁻) generation. These highly oxidative/nitrative compounds further induce mitochondrial ROS/RNS generation, electron transport chain (ETC) dysfunction, and mtDNA damage. Collectively, these events are thought to contribute to liver steatosis. To maintain mitochondrial population and quality, the cell stimulates mitochondrial biogenesis and mitophagy pathways. Mitochondrial biogenesis is a complex process that is controlled by communication between the nucleus and the organelle to activate transcription factors that control fusion and fission processes. DRP1 and OPA1 are fission proteins located on the mitochondrial outer and inner membranes, respectively that divide and segregate damaged mitochondria to increase the population of healthy mitochondria. In contrast, mitophagy is initiated by the formation of cytoplasmic double membrane structures that recognize damaged mitochondria. Further, expansion of the autophagosomal structures is dependent on the conversion of LC3-I to LC3-II, and insertion of LC3-II into the autophagosomal membranes. Completion of autophagic flux requires fusion of autophagosomes with lysosomes, where damaged mitochondria are degraded and cleared from the cell. Mitoquinone (MitoQ), a mitochondrial targeted antioxidant has been shown to prevent alcoholic liver disease-mediated oxidative and nitrative stress and steatosis, supporting the pivotal role of mitochondrial oxidants in alcoholic liver disease pathogenesis.