Restoring cellular NAD(P)H levels by PPARα and LXRα stimulation to improve mitochondrial complex I deficiency

Life Sci. 2022 Jul 1;300:120571. doi: 10.1016/j.lfs.2022.120571. Epub 2022 Apr 22.


Mitochondrial complex I (CI), the first multiprotein enzyme complex of the oxidative phosphorylation system, plays a crucial role in cellular energy production. CI deficiency is associated with a variety of clinical phenotypes, including Leigh syndrome. At the cellular level, an increased NAD(P)H concentration is one of the hallmarks in CI-deficiency.

Aims: Here, we aimed to attenuate increased NAD(P)H levels by stimulation of ATP-dependent cassette (ABC)A1 and ABCG1-mediated cellular cholesterol efflux with various PPARα and LXRα agonists.

Main methods: Mitochondrial CI-deficient fibroblasts and chemically-induced CI-deficient HeLa cells were used to study the dose-dependent effects of various PPARα and LXRα agonists on cellular NAD(P)H levels and cholesterol efflux.

Key findings: In patient-derived mitochondrial CI-deficient fibroblasts, GW590735, astaxanthin, oleoylethanolamide, and GW3965 significantly reduced the enhanced NAD(P)H levels in CI-deficient fibroblasts. Similar effects were observed in chemically-induced CI-impaired HeLa cells, in which BMS-687453, Wy14643, GW7647, T0901317, DMHCA also demonstrated a beneficial effect. Surprisingly, no effect on ABCA1- and ABCG1-mediated cholesterol efflux in HeLa cells and fibroblasts was found after treatment with these compounds. The reduction in NAD(P)H levels by GW590735 could be partially reversed by inhibition of fatty acid synthase and β-oxidation, which suggests that its beneficial effects are possibly mediated via stimulation of fatty acid metabolism rather than cholesterol efflux.

Significance: Collectively, PPARα and LXRα stimulation resulted in attenuated cellular NAD(P)H levels in CI-impaired HeLa cells and patient-derived fibroblasts and could eventually have a therapeutic potential in CI deficiency.

Keywords: Liver X receptor α; Mitochondrial complex I deficiency; Nicotinamide adenine dinucleotide (phosphate); Peroxisome proliferator activated receptor α; Redox state.

MeSH terms

  • ATP Binding Cassette Transporter 1 / metabolism
  • Cholesterol / metabolism
  • Electron Transport Complex I / deficiency
  • HeLa Cells
  • Humans
  • Liver X Receptors / metabolism
  • Mitochondrial Diseases
  • NAD* / metabolism
  • PPAR alpha* / metabolism


  • ATP Binding Cassette Transporter 1
  • Liver X Receptors
  • PPAR alpha
  • NAD
  • Cholesterol
  • Electron Transport Complex I

Supplementary concepts

  • Mitochondrial complex I deficiency