Mitochondrial complex IV disruption is a detrimental pathology conferring ssusceptibility to alzheimer's disease

Mitochondrial complex IV (CIV) is an integral part of the mitochondrial electron transport chain (ETC) and plays a pivotal role in maintaining mitochondrial function. In contrast to the long-standing recognition of its dysfunction in Alzheimer's disease (AD), the exact role of CIV deficit in the pathogenesis of this neurodegenerative disorder remains poorly defined. In this study, by incorporating clinical resources, mouse- and human-based models of AD risk, and a genetic approach to bypass defective CIV via the ectopic expression of alternative oxidase (AOX), we examined whether CIV deficits are a pathogenic driver of or a beneficial adaptation to AD-associated pathologies. Our results showed a clinicopathological association between neuronal CIV dysfunction and pathological characteristics of AD. Further experiments linked defective CIV to the development of mitochondrial dysfunction and synaptic loss in the tested mouse- and human-based models of AD risk. In addition, a reciprocal relationship between CIV dysfunction and amyloid pathology was determined. Lastly, a proteome-wide association study (PWAS) using genetic data from large-scale AD cohorts identified that downregulation of COX11, a crucial CIV assembly factor, confers susceptibility to AD risk. Collectively, our findings suggest that CIV dysfunction is a detrimental pathology contributing to AD-associated mitochondrial and neuronal damage. The dual role of CIV dysfunction, both as a consequence of and a contributor to amyloid toxicity in AD pathogenesis, further justifies the therapeutic potential of strategies targeting CIV deficits to diversify the tools for prevention and treatment of this neurodegenerative disorder.