Current Issues in Molecular Biology (Aug 2024)

The Role of Sirtuin-1 Isoforms in Regulating Mitochondrial Function

  • Pankaj Patyal,
  • Fathima S. Ameer,
  • Ambika Verma,
  • Xiaomin Zhang,
  • Gohar Azhar,
  • Jyotsna Shrivastava,
  • Shakshi Sharma,
  • Rachel Zhang,
  • Jeanne Y. Wei

DOI
https://doi.org/10.3390/cimb46080522
Journal volume & issue
Vol. 46, no. 8
pp. 8835 – 8851

Abstract

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The sirtuin-1 (SIRT1) gene contains multiple exons that usually undergo alternative splicing. The exclusion of one or more exons causes domain loss in the alternatively spliced isoforms and may change their functions. However, it is not completely established to what extent the loss of a non-catalytic domain could affect its regulatory function. Using muscle cells and SIRT1-knockout cells, we examined the function of the constitutively spliced isoform (SIRT1-v1) versus the alternatively spliced isoforms SIRT1-v2 and SIRT1-v3 that had lost part of the N-terminal region. Our data indicate that partial loss of the N-terminal domains in SIRT1-v2 and SIRT1-v3 attenuated their function. The full-length SIRT1-v1 significantly increased the oxidative phosphorylation and ATP production rate. Furthermore, SIRT1-v1 specifically upregulated the mitochondrial respiratory complex I without affecting the activity of complexes II, III, and IV. Additionally, domain loss affected the regulation of site-specific lysine acetylation in the histone H4 protein, the gene expression of respiratory complex I subunits, and the metabolic balance of oxidative phosphorylation versus glycolysis. Since alternatively spliced isoforms tend to increase with advancing age, the impact of SIRT1 isoforms on mitochondrial respiratory complexes warrants further investigation.

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