Mitochondrial oxidative function in NAFLD: Friend or foe?
Michael Shum1, Jennifer Ngo2, Orian S Shirihai3
1Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Dr., Los Angeles, CA, 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Dr., Los Angeles, CA, 90095, USA; Molecular Biology Institute at UCLA, Los Angeles, CA, 90095, USA.
Molecular Metabolism
|December 4, 2020
Summary
Mitochondrial function in non-alcoholic fatty liver disease (NAFLD) may increase to meet metabolic demands, not decrease due to damage. Targeting mitochondrial fuel preference and specific antioxidants offers new therapeutic strategies for NAFLD and insulin resistance.
Area of Science:
- Hepatology
- Mitochondrial Biology
- Metabolic Diseases
Background:
- Mitochondrial oxidative function is crucial in non-alcoholic fatty liver disease (NAFLD) and insulin resistance (IR).
- Emerging evidence suggests NAFLD and IR elevate, rather than decrease, mitochondrial function to meet increased demands from lipogenesis and gluconeogenesis.
- Mitochondria influence hepatic insulin sensitivity and lipogenesis via redox-sensitive signaling pathways.
Purpose of the Study:
- To review conflicting studies on the impact of NAFLD and hyperglycemia on hepatic mitochondrial oxidative capacity.
- To explore mechanisms of mitochondrial heterogeneity within liver cells and their role in NAFLD.
- To discuss the function of endogenous antioxidants in regulating mitochondrial hydrogen peroxide (H2O2) release and redox signaling.
Main Methods:
- Literature review of studies investigating mitochondrial function in NAFLD.
- Analysis of mechanisms regulating mitochondrial heterogeneity.
- Examination of the role of endogenous antioxidants and their subcellular localization.
Main Results:
- Contradictory findings exist regarding whether NAFLD/hyperglycemia increases or decreases mitochondrial oxidative capacity.
- Mitochondrial heterogeneity within cells may dictate their specific roles in NAFLD pathogenesis.
- The subcellular location of antioxidants is critical in modulating their effects on NAFLD and redox signaling.
Conclusions:
- Therapeutic strategies for NAFLD should focus on mitochondrial fuel preference, not solely on respiration.
- Modulating maladaptive antioxidants, rather than physiological redox signaling, may preserve hepatic insulin signaling.
- Targeting antioxidant compartmentalization and specific mitochondrial subpopulations presents novel intervention points for NAFLD treatment.
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