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

• Published in: Cell death & disease 2023-02, Vol.14 (2), p.110-110, Article 110
• Main Authors: Ploumi, Christina, Kyriakakis, Emmanouil, Tavernarakis, Nektarios
• Format: Article
• Language: English
• Subjects: 13/2; 13/89; 13/95; 14/19; 38/35; 42/109; 42/34; 42/41; 45/77; 631/80/39/2346; 631/80/642/333; 631/80/82/23; 64/11; Aging; Aging - metabolism; Animals; Antibodies; Apoptosis; Autophagy; Autophagy - genetics; Biochemistry; Bioenergetics; Biomedical and Life Sciences; Caenorhabditis elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cell Biology; Cell Culture; Cell death; Homeostasis; Immunology; Iron; Life Sciences; Life span; Longevity; Mitochondria; Mitochondria - metabolism; Nematodes; Proteostasis
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-023-05638-x

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.