Coupling of autophagy and the mitochondrial intrinsic apoptosis pathway modulates proteostasis and ageing in Caenorhabditis elegans

Mitochondria preserve metabolic homeostasis and integrate stress signals, to trigger cytoprotective, or cell death pathways. Mitochondrial homeostasis and function decline with age. The mechanisms underlying the deterioration of mitochondrial homeostasis during ageing, or in age-associated pathologies, remain unclear. Here, we show that CISD-1, a mitochondrial iron-sulfur cluster binding protein, implicated in the pathogenesis of Wolfram neurodegenerative syndrome type 2, modulates longevity in the nematode Caenorhabditis elegans by engaging autophagy and the mitochondrial intrinsic apoptosis pathway. The anti-apoptotic protein CED-9 is the downstream effector that mediates CISD-1-dependent effects on proteostasis, neuronal integrity and lifespan. Moreover, intracellular iron abundance is critical for CISD-1 function, since mild iron supplementation is sufficient to decelerate ageing and partly ameliorate the disturbed mitochondrial bioenergetics and proteostasis of CISD-1 deficient animals. Our findings reveal that CISD-1 serves as a mechanistic link between autophagy and the apoptotic pathway in mitochondria to differentially modulate organismal proteostasis and ageing, and suggest novel approaches which could facilitate the treatment of Wolfram Syndrome or related diseases.

Automated summary

Mitochondria play a crucial role in maintaining metabolic balance and responding to stress signals through cytoprotective or cell death pathways. However, the mechanisms underlying the decline of mitochondrial homeostasis during aging or age-related diseases are still not fully understood. In this study, CISD-1, a mitochondrial iron-sulfur cluster binding protein, was found to regulate longevity in Caenorhabditis elegans through autophagy and the mitochondrial intrinsic apoptosis pathway. The downstream effector protein CED-9 mediates the effects of CISD-1 on proteostasis, neuronal integrity, and lifespan. Additionally, maintaining intracellular iron abundance is essential for CISD-1 function, as mild iron supplementation can slow down aging and improve mitochondrial bioenergetics and proteostasis in CISD-1 deficient animals. These findings provide insights into the mechanistic links between autophagy and the apoptotic pathway in mitochondria, and offer potential therapeutic strategies for Wolfram Syndrome and related diseases.