Multifaceted roles of mitochondrial stress responses under ETC dysfunction - repair, destruction and pathogenesis.

Electron transport chain (ETC) dysfunction is a common feature of mitochondrial diseases and induces severe cellular stresses, including mitochondrial membrane potential (Δψ m ) reduction, mitochondrial matrix acidification, metabolic derangements and proteostatic stresses. Extensive studies of ETC dysfunction in yeast, Caenorhabditis elegans, cultured cells and mouse models have revealed multiple mitochondrial stress response pathways. Here, we summarise the current understanding of the triggers, sensors, signalling mechanisms and the functional outcomes of mitochondrial stress responses in different species. We highlight Δψ m reduction as a major trigger of stress responses in different species, but the responses are species-specific and the outcomes are context-dependent. ETC dysfunction elicits a mitochondrial unfolded protein response (UPR mt ) to repair damaged mitochondria in C. elegans, and activates a global adaptive programme to maintain Δψ m in yeast. Yeast and C. elegans responses are remarkably similar at the downstream responses, although they are activated by different signalling mechanisms. UPR mt generally protects ETC-defective worms, but its constitutive activation is toxic for wildtype worms and worms carrying mutant mtDNA. In contrast to lower organisms, ETC dysfunction in mammals mainly activates a mitochondrial integrated stress response (ISR mt ) to reprogramme metabolism and a PINK1-Parkin mitophagy pathway to degrade damaged mitochondria. Accumulating in vivo results suggest that the ATF4 branch of ISR mt exacerbates metabolic derangements to accelerate mitochondrial disease progression. The in vivo roles of mitophagy in mitochondrial diseases are also context-dependent. These results thus reveal the common and unique aspects of mitochondrial stress responses in different species and highlight their multifaceted roles in mitochondrial diseases.