Researchers at the University of Birmingham have identified the molecular basis of metabolic diseases linked to autophagy
A joint study by Sovan Sarkar at the University of Birmingham and Viktor Korolchuk at Newcastle University has shown a role of autophagy, a cellular catabolic process, in ensuring cell survival by preserving levels of nicotinamide adenine dinucleotide (NAD) and NADH.
Malfunction of autophagy in age-related human pathologies contributes to tissue degeneration through a poorly understood mechanism. Using autophagy-deficient cell models, depletion of NADH has been identified via unbiased metabolomics to be correlating with cell viability in respiring cells. NAD depletion is found to be triggered by sequential events involving loss of mitophagy, increased oxidative stress, DNA damage and hyperactivation of PARP/SIRT NADases, leading to uncontrolled NAD consumption and eventually, apoptosis. This study provides a mechanistic link between autophagy and NAD metabolism, and identifies targets in human diseases associated with autophagic, lysosomal, and mitochondrial dysfunction. Pharmacological and genetic interventions targeting several key elements of this cascade improved the survival of autophagy-deficient cells.
- Loss of autophagy in respiring cells causes a metabolic deficit and mitochondrial damage
- NADases of PARP and Sirtuin families are hyperactive in autophagy-deficient cells
- NAD depletion contributes to death of autophagy-/mitophagy-deficient cells
This study was recently published and is featured on the cover of Developmental Cell.
Developmental Cell 57:2584-2598 e2511 (2022). Kataura T, L Sedlackova, EG Otten, R Kumari, D Shapira, F Scialo, R Stefanatos, K Ishikawa, G Kelly, E Seranova, C Sun . . . . . .S Sarkar and VI Korolchuk. Autophagy promotes cell survival by maintaining NAD levels. DOI: 10.1016/j.devcel.2022.10.008
https://www.cell.com/developmental-cell/fulltext/S1534-5807(22)00760-2 DOI: 10.1016/j.devcel.2022.10.008