Mitochondria are semi-autonomous organelles of prokaryotic origin that are postulated to have been acquired by eukaryotic cells through an early endosymbiotic event. Except for their main role in energy production, they are also implicated in fundamental cellular processes, including ion homeostasis, lipid metabolism, and initiation of apoptotic cell death. Perturbed mitochondrial function has been correlated with severe human pathologies such as type-2 diabetes, cardiovascular, and neurodegenerative diseases. Thus, proper mitochondrial physiology is a prerequisite for health and survival. Cells have developed sophisticated and elaborate mechanisms to adapt to stress conditions and alterations in metabolic demands, by regulating mitochondrial number and function. Hence, the generation of new and the removal of damaged or unwanted mitochondria are highly regulated processes that need to be accurately coordinated for the maintenance of mitochondrial and cellular homeostasis. Here, we survey recent research findings that advance our understanding and highlight the importance of the underlying molecular mechanisms. Abbreviations AGO2, argonaute 2; AMPK, AMP-activated protein kinase; ATFS1, activating transcription factor associated with stress 1; Atg32, autophagyrelated 32; Bcl-2, B-cell lymphoma 2; BCL2L13, Bcl-2-like 13; Bnip3, Bcl-2/adenovirus E1B 19kDa-interacting protein 3; Bnip3L/Nix, Bnip3-like/NIP3-like protein X; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; CerS1, ceramide synthase 1; CL, cardiolipin; COXIV, cytochorome C oxidase subunit IV; CREB, cAMP response element-binding protein; DAF-16, abnormal DAuer Formation 16; DCT-1, DAF-16/ FOXO controlled germline tumor-affecting 1; DRP1, dynamin-related protein; ER, endoplasmic reticulum; ERRα, estrogen-related receptor alpha; FOXO, forkhead box O; FUNDC1, FUN14 domain-containing 1; GABARAP, GABA(A) receptor-associated protein; GABP, GA-binding protein transcription factor; GCN5L1, general control of amino acid synthesis 6-like 1; HO-1, heme oxygenase-1; ILS, insulin-like signaling; IMM, inner mitochondrial membrane; IMS, intermembrane space; KEAP1, Kelch-Like ECH-associated protein 1; LC3-II, lipidated form of LC3; LC3, light chain 3; LIR, LC3-interacting region; MAPK, mitogen-activated protein kinase; Mba1, multi-copy Bypass of AFG3; MDVs, mitochondrial-derived vesicles; MFN2, mitofusin 2; miRNA, micro RNA; MPP, mitochondrial processing peptidase; MtCK, mitochondrial creatine kinase; mtDNA, mitochondrial DNA; MTHFD2, methylenetetrahydrofolate dehydrogenase (NADP + dependent) 2; mTOR, mechanistic target of rapamycin; NAC, nascent polypeptide-associated complex; NBR1, neighbor of BRCA 1 gene 1; NDP52, nuclear dot protein 52 kDa; NDPK-D, nucleoside diphosphatate kinase-D; NFE2L, nuclear factor erythroid 2-like; NRF, nuclear respiratory factor; OMM, outer mitochondrial membrane; OPA1, optic atrophy 1; p62, nucleoporin 62; PARIS, Parkin-interacting substrate; PARL, presenilin-associated rhomboid-like protease; PGAM-5, phosphoglycerate mutase homolog-5; PGC1α...

The elimination of abnormal and dysfunctional cellular constituents is an essential prerequisite for nerve cells to maintain their homeostasis and proper function. This is mainly achieved through autophagy, a process that eliminates abnormal and dysfunctional cellular components, including misfolded proteins and damaged organelles. Several studies suggest that age-related decline of autophagy impedes neuronal homeostasis and, subsequently, leads to the progression of neurodegenerative disorders due to the accumulation of toxic protein aggregates in neurons. Here, we discuss the involvement of autophagy perturbation in neurodegeneration and present evidence indicating that upregulation of autophagy holds potential for the development of therapeutic interventions towards confronting neurodegenerative diseases in humans.

One-carbon metabolism (OCM) is a network of biochemical reactions delivering one-carbon units to various biosynthetic pathways. The folate cycle and methionine cycle are the two key modules of this network that regulate purine and thymidine synthesis, amino acid homeostasis, and epigenetic mechanisms. Intersection with the transsulfuration pathway supports glutathione production and regulation of the cellular redox state. Dietary intake of micronutrients, such as folates and amino acids, directly contributes to OCM, thereby adapting the cellular metabolic state to environmental inputs. The contribution of OCM to cellular proliferation during development and in adult proliferative tissues is well established. Nevertheless, accumulating evidence reveals the pivotal role of OCM in cellular homeostasis of non-proliferative tissues and in coordination of signaling cascades that regulate energy homeostasis and longevity. In this review, we summarize the current knowledge on OCM and related pathways and discuss how this metabolic network may impact longevity and neurodegeneration across species.

Autophagy is a universal cellular homeostatic process, required for the clearance of dysfunctional macromolecules or organelles. This self-digestion mechanism modulates cell survival, either directly by targeting cell death players, or indirectly by maintaining cellular balance and bioenergetics. Nevertheless, under acute or accumulated stress, autophagy can also contribute to promote different modes of cell death, either through highly regulated signalling events, or in a more uncontrolled inflammatory manner. Conversely, apoptotic or necroptotic factors have also been implicated in the regulation of autophagy, while specific factors regulate both processes. Here, we survey both earlier and recent findings, highlighting the intricate interaction of autophagic and cell death pathways. We, Furthermore, discuss paradigms, where this cross-talk is disrupted, in the context of disease.

Aging is the major risk factor for several life‐threatening pathologies and impairs the function of multiple cellular compartments and organelles. Age‐dependent deterioration of nuclear morphology is a common feature in evolutionarily divergent organisms. Lipid droplets have been shown to localize in most nuclear compartments, where they impinge on genome architecture and integrity. However, the significance of progressive nuclear lipid accumulation and its impact on organismal homeostasis remain obscure. Here, we implement non‐linear imaging modalities to monitor and quantify age‐dependent nuclear lipid deposition in Caenorhabditis elegans. We find that lipid droplets increasingly accumulate in the nuclear envelope, during aging. Longevity‐promoting interventions, such as low insulin signaling and caloric restriction, abolish the rate of nuclear lipid accrual and decrease the size of lipid droplets. Suppression of lipotoxic lipid accumulation in hypodermal and intestinal nuclei is dependent on the transcription factor HLH‐30/TFEB and the triglyceride lipase ATGL‐1. HLH‐30 regulates the expression of ATGL‐1 to reduce nuclear lipid droplet abundance in response to lifespan‐extending conditions. Notably, ATGL‐1 localizes to the nuclear envelope and moderates lipid content in long‐lived mutant nematodes during aging. Our findings indicate that the reduced ATGL‐1 activity leads to excessive nuclear lipid accumulation, perturbing nuclear homeostasis and undermining organismal physiology, during aging.

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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.

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