Mitochondrial membrane dynamics dictated by MT-ATP6 synthesis fidelity Brendan J. Battersby Institute of Biotechnology, University of Helsinki, Helsinki, Finland
Mitochondria are enveloped by two dynamic membranes whose shape is critical for function and in the pathogenesis of human disease. The dynamin-related GTPase OPA1 plays a central role coordinating the dynamics and ultrastructure of the inner membrane. A key regulatory step is stress-induced proteolytic processing of OPA1 that severs the tether to the inner membrane thereby releasing the protein into a soluble pool to stimulate remodelling of mitochondrial morphology. This mitochondrial stress response is an early and major event in the progression and severity of selected neurodegenerative disorders, thus could be an attractive therapeutic target to modulate. However, our understanding of induced OPA1 proteolysis and consequences derives largely from studies where mitochondrial stress is generated by the addition of severely toxic compounds, such as the proton ionophore CCCP to dissipates the membrane potential. The rationale why these insults or damage to mitochondrial function trigger OPA1 processing is currently unknown. Here, we identify the origin of the molecular trigger endogenous to mitochondria that activates this cascade and establish the rationale of this regulation to organelle homeostasis. We show defects in folding and quality control of MT-ATP6 nascent chains synthesized by mitochondrial ribosomes generated proteotoxicity in the inner membrane stimulating OMA1 proteolytic processing of OPA1 and remodeling of mitochondrial morphology. Activation of this response attenuated protein synthesis on mitochondrial ribosomes, providing negative feedback regulation of mitochondrial gene expression analogous to a circuit breaker that we propose acts to prevent further insults to membrane integrity. Lastly, we discovered a small molecule that can modulate this membrane stress response and paves a way forward for patient therapy.
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