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

Abstract

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.

Neurotrophic factor MANF regulates autophagy and lysosome function to promote proteostasis inC. elegans

“…The role of MANF-1 in lysosome-mediated signaling and the involvement of HLH-30/TFEB in this process led us to investigate the role of LGG-1/Atg8/LC3 and SQST-1/p62 in regulating autophagy [40, [59][60][61][62]. Although an increase in LGG-1 and SQST-1 puncta may be caused by a blockage of autophagy, a reduction in both types of puncta is indicative of an increase in autophagic flux.…”

“…The role of MANF-1 in lysosome-mediated signaling and involvement of HLH-30/TFEB in this process led us to investigate the roles of LGG-1/Atg8/LC3 and SQST-1/p62 that regulate autophagy (Palmisano and Meléndez 2016;Henis-Korenblit and Meléndez 2019;Ploumi et al 2021;Ploumi et al 2023). While an increase in LGG-1 and SQST-1 puncta may be caused by a block in autophagy (Palmisano and Meléndez 2016;Henis-Korenblit and Meléndez 2019;Ploumi et al 2021;Ploumi et al 2023), a reduction in both is indicative of an increase in autophagic flux. We found that MANF-1 OE animals had reduced LGG-1::GFP and SQST-1::GFP puncta, suggesting that MANF-1 promotes autophagy.…”

Nurturing longevity through natural compounds: Where do we stand, and where do we go?

“…Chaperone‐mediated protein folding and quality control mechanisms deteriorate with aging and predispose the organism to reduction in both healthspan and lifespan (Ploumi et al., 2023). Impaired proteostasis is characteristic of various age‐related diseases such as AD and Parkinson's disease, atherosclerosis, and amyothrophic lateral sclerosis (Tan et al., 2022).…”

“…The NEET family of iron–sulfur (Fe–S) cluster‐binding proteins (known as CISD proteins) is predominantly presented within the mitochondria. Depletion of CISD proteins reduces the lifespan, neuronal integrity, and proteostasis in C. elegans that could be reversed by inhibition of cell death abnormality gene 9, through induction of autophagy (Ploumi et al., 2023).…”

“…Autophagy is a recycling process that takes place at a basal physiological level in virtually every cell. Properly functional autophagy plays the role of adaptive quality control mechanism to alternations in nutrient availability and cellular stress (D. Park et al., 2016; Ploumi et al., 2023; Tuohetaerbaike et al., 2020). However, it could be accelerated by stress triggers such as CR, oxidative stress, endoplasmic reticulum stress, hypoxia, or inflammation (M. Wu et al., 2021; Xiang et al., 2022).…”