Omega-3 Fatty Acids Upregulate SIRT1/3, Activate PGC-1α via Deacetylation, and Induce Nrf1 Production in 5/6 Nephrectomy Rat Model

Abstract

Mitochondrial dysfunction contributes to the pathogenesis of kidney injury related with cardiovascular disease. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) protects renal tubular cells by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2). AMP-activated protein kinase (pAMPK)-mediated phosphorylation and sirtuin 1/3 (SIRT1/3)-mediated deacetylation are required for PGC-1α activation. In the present study, we aimed to investigate whether omega-3 fatty acids (FAs) regulate the expression of mediators of mitochondrial biogenesis in 5/6 nephrectomy (Nx) rats. Male Sprague-Dawley rats were assigned to the following groups: sham control, Nx, and Nx treated with omega-3 FA. The expression of PGC-1α, phosphorylated PGC-1α (pPGC-1α), acetylated PGC-1α, and factors related to mitochondrial biogenesis was examined through Western blot analysis. Compared to the control group, the expression of PGC-1α, pAMPK, SIRT1/3, Nrf1, mTOR, and Nrf2 was significantly downregulated, and that of Keap 1, acetylated PGC-1α, and FoxO1/3, was significantly upregulated in the Nx group. These changes in protein expression were rescued in the omega-3 FA group. However, the expression of pPGC-1α was similar among the three groups. Omega-3 FAs may involve mitochondrial biogenesis by upregulating Nrf1 and Nrf2. This protective mechanism might be attributed to the increased expression and deacetylation of PGC-1α, which was triggered by SIRT1/3.

Molybdenum and Cadmium Co-induce Mitochondrial Quality Control Disorder via FUNDC1-Mediated Mitophagy in Sheep Kidney

“…SIRT1 and SIRT3 are crucial coordinators of PGC-1α, adjusting the biogenesis and function of the mitochondria (47). FOXO1 and FOXO3 bind to the PGC-1α promoter and enhance its transcription (48). We found that the Mo and/or Cd treatment observably decreased both the mRNA and protein levels of PGC-1α, and markedly reduced the mRNA levels of SIRT1, SIRT3, FOXO1 and FOXO3.…”

Estrogen signaling as a bridge between the nucleus and mitochondria in cardiovascular diseases

“…Sirt3-KO mice showed lower palmitate oxidation, lower respiratory capacity, lower ATP synthesis, and abnormal lipid accumulation, with impaired mitochondrial and contractile cardiac function ( Chen T. et al, 2015 ; Koentges et al, 2015 ). Finally, low SIRT-3 levels are also correlated with a down-regulation of PGC1-α ( Yu et al, 2017 ), suggesting the conservation of the reported PGC-1α/SIRT3 protective axis ( Son et al, 2021 ) due to SIRT3 enhanced activity ( Figure 3 ). Thus, all the listed findings highlight the importance of elucidate the hypothetical ERα or ERRs-SIRT3-mtUPR mitochondrial cardioprotective pathway in different CVDs as a new important axis in the cardioprotection triggered by estrogens.…”

PGC-1α activity and mitochondrial dysfunction in preterm infants

“…Additionally, breast milk is an excellent source of omega 3 for newborn infants ( Berenhauser et al, 2012 ; Samuel et al, 2020 ). The positive effect of omega 3 fatty acids is largely attributed to PGC-1α activation through the SIRT1/3 pathways ( Son et al, 2021 ). Omega 3 fatty acids are essential for brain and retinal development during the postnatal period and decreased levels are associated with increased risk for neonatal morbidities such as respiratory disease, decline in cognitive and motor abilities, and decreased postnatal growth ( Martin et al, 2011 ; Bernardi et al, 2012 ; Fink et al, 2016 ; Lapillonne and Moltu, 2016 ; Gould et al, 2018 ).…”

“…Limited studies have investigated the mechanism for the protective effect of omega 3 supplementation. However, recent studies report that it rescues PGC-1α, SIRT1/3, NRF-1/2, and AMPK protein expression in nephrectomy rats, and significantly increases total mitochondrial content in rodent skeletal muscle tissue and human skeletal muscle cells ( Vaughan et al, 2012 ; Liu et al, 2019b ; Son et al, 2021 ). Omega 3 fatty acids are safe and well-tolerated orally in infants and children hence, further mechanistic studies exploring its effect on PGC-1α signaling in the brain and lung during development would enhance our understanding of the therapeutic potential in preterm infants.…”