P46Shc Inhibits Mitochondrial ACAA2 Thiolase, Exacerbating Mitochondrial Injury and Inflammation in Aging Livers

Mitochondrial maladaptation and dysfunction contribute to the progression of metabolic dysfunction-associated steatohepatitis (MASH). We recently implicated the induction of Shc in progressive MASH during aging and the cytoplasmic p52Shc isoform in the activation of redox enzyme NOX2. The mitochondrial Shc isoform p46Shc was shown to repress acetyl-Coenzyme A acyltransferase 2 (ACAA2) in vitro. ACAA2 is a key enzyme for lipid β-oxidation; however, the metabolic consequences of in vivo p46Shc induction were unknown. We generated p46Shc-inducible mice, these and littermate controls were aged, and fed chow or fast-food diet (high-fat & high-fructose). p46Shc induction increased liver injury, inflammation and lipid peroxidation. p46Shc overexpression didn't significantly change liver triglycerides. On EM studies, mitochondria were swollen with aberrant cristae. p46Shc induction reduced mitochondrial O2 consumption as measured by Oroboros, as well as suppressed the production of β-hydroxybutyrate, the central metabolite of therapeutic ketosis. Mitochondria exhibited increased production of reactive oxidative species. In contrast, when the dominant negative p46Shc was expressed, this reduced ACAA2 thiolase activity, improved β-oxidation, and reduced lipid peroxidation and production of reactive oxidative species. In summary, these studies support the concept that p46Shc induction in aging represses ACAA2, resulting in decreased mitochondrial β-oxidation and increased lipid peroxidation. Maintaining β-oxidation and ketogenesis could prevent liver injury, and targeting Shc-related maladaptive responses could be a successful therapeutic strategy in aging/MASH.