Mukherjee 2021 JCI Insight
| Mukherjee S, Mo J, Paolella LM, Perry CE, Toth J, Hugo MM, Chu Q, Tong Q, Chellappa K, Baur JA (2021) SIRT3 is required for liver regeneration but not for the beneficial effect of nicotinamide riboside. JCI Insight 6:e14719. |
Mukherjee Sarmistha, Mo James, Paolella Lauren M, Perry Caroline E, Toth Jade, Hugo Mindy M, Chu Qingwei, Tong Qian, Chellappa Karthikeyani, Baur Joseph A (2021) JCI Insight
Abstract: Liver regeneration is critical to survival after traumatic injuries, exposure to hepatotoxins, or surgical interventions, yet the underlying signaling and metabolic pathways remain unclear. In this study, we show that hepatocyte-specific loss of the mitochondrial deacetylase SIRT3 drastically impairs regeneration and worsens mitochondrial function after partial hepatectomy. Sirtuins, including SIRT3, require NAD as a cosubstrate. We previously showed that the NAD precursor nicotinamide riboside (NR) promotes liver regeneration, but whether this involves sirtuins has not been tested. Here, we show that despite their NAD dependence and critical roles in regeneration, neither SIRT3 nor its nuclear counterpart SIRT1 is required for NR to enhance liver regeneration. NR improves mitochondrial respiration in regenerating WT or mutant livers and rapidly increases oxygen consumption and glucose output in cultured hepatocytes. Our data support a direct enhancement of mitochondrial redox metabolism as the mechanism mediating improved liver regeneration after NAD supplementation and exclude signaling via SIRT1 and SIRT3. Therefore, we provide the first evidence to our knowledge for an essential role for a mitochondrial sirtuin during liver regeneration and insight into the beneficial effects of NR. • Keywords: Fatty acid oxidation, Hepatology, Metabolism, Mitochondria, Molecular pathology • Bioblast editor: Reiswig R • O2k-Network Lab: US PA Philadelphia Baur JA
Labels: MiParea: Respiration, Genetic knockout;overexpression
Organism: Mouse
Tissue;cell: Liver
Preparation: Isolated mitochondria
Coupling state: OXPHOS
Pathway: F, N, S, CIV, ROX
HRR: Oxygraph-2k
2021-07
