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Comment
. 2023 Aug;19(8):2395-2397.
doi: 10.1080/15548627.2023.2165753. Epub 2023 Feb 1.

Metabolic function of autophagy is essential for cell survival

Affiliations
Comment

Metabolic function of autophagy is essential for cell survival

Lucia Sedlackova et al. Autophagy. 2023 Aug.

Abstract

Age-related human pathologies present with a multitude of molecular and metabolic phenotypes, which individually or synergistically contribute to tissue degeneration. However, current lack of understanding of the interdependence of these molecular pathologies limits the potential range of existing therapeutic intervention strategies. In our study, we set out to understand the chain of molecular events, which underlie the loss of cellular viability in macroautophagy/autophagy deficiency associated with aging and age-related disease. We discover a novel axis linking autophagy, a cellular waste disposal pathway, and a metabolite, nicotinamide adenine dinucleotide (NAD). The axis connects multiple organelles, molecules and stress response pathways mediating cellular demise when autophagy becomes dysfunctional. By elucidating the steps on the path from efficient mitochondrial recycling to NAD maintenance and ultimately cell viability, we highlight targets potentially receptive to therapeutic interventions in a range of genetic and age-related diseases associated with autophagy dysfunction.Abbreviations: IMM: inner mitochondrial membrane; NAD: nicotinamide dinucleotide; OXPHOS: oxidative phosphorylation; PARP: poly(ADP-ribose) polymerase; ROS: reactive oxygen species.

Keywords: Aging; DNA damage; NAD; PARP; ROS; autophagy; mitochondria; mitophagy; sirtuins.

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Conflict of interest statement

V.I.K is a Scientific Advisor for Longaevus Technologies.

Figures

Figure 1.
Figure 1.
Autophagy promotes cell survival by maintaining intracellular NAD pools. Mitochondrial recycling by autophagy prevents a cascade of deleterious events downstream of mitochondrial dysfunction. (A) In autophagy-competent cells, recycling of mitochondria maintains a healthy population of organelles (1), which can draw on plentiful intracellular NAD pools (2) to support their metabolism and maintain cell survival (3). (B) In autophagy deficiency (1), accumulation of dysfunctional mitochondria results in elevated levels of ROS (2), which persistently activate stress-response enzymes of the SIRT and PARP families (3). Uncontrolled cleavage of NAD by these enzymes drives the exhaustion of intracellular NAD pools (4). Loss of available NAD negatively affects mitochondrial metabolism (5), which triggers IMM depolarization and apoptosis (6).

Comment on

  • Autophagy promotes cell survival by maintaining NAD levels.
    Kataura T, Sedlackova L, Otten EG, Kumari R, Shapira D, Scialo F, Stefanatos R, Ishikawa KI, Kelly G, Seranova E, Sun C, Maetzel D, Kenneth N, Trushin S, Zhang T, Trushina E, Bascom CC, Tasseff R, Isfort RJ, Oblong JE, Miwa S, Lazarou M, Jaenisch R, Imoto M, Saiki S, Papamichos-Chronakis M, Manjithaya R, Maddocks ODK, Sanz A, Sarkar S, Korolchuk VI. Kataura T, et al. Dev Cell. 2022 Nov 21;57(22):2584-2598.e11. doi: 10.1016/j.devcel.2022.10.008. Dev Cell. 2022. PMID: 36413951 Free PMC article.

References

    1. Kataura T, Sedlackova L, EG O, et al. Autophagy promotes cell survival by maintaining NAD levels. Dev Cell. 2022. Nov 21;57(22):2584–2598.e11. - PMC - PubMed

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