<i>Sirt3</i> Deficiency Shortens Life Span and Impairs Cardiac Mitochondrial Function Rescued by <i>Opa1</i> Gene Transfer

<b><i>Aims:</i></b> Sirtuins, a family of NAD⁺-dependent deacetylases, are recognized as nondispensable regulators of aging processes. Sirtuin 3 (SIRT3) is the main mitochondrial deacetylase that maintains mitochondrial bioenergetics, an essential prerequisite for healthy aging. In this study, using <i>Sirt3</i> knockout (<i>Sirt3^-/-</i>) mice, we sought to establish whether <i>Sirt3</i> deficiency affected life span, an endpoint that has never been tested formally in mammals, and uncover the mechanisms involved in organ damage associated with aging. <b><i>Results:</i></b><i>Sirt3^-/-</i> mice experienced a shorter life span than wild-type mice and severe cardiac damage, characterized by hypertrophy and fibrosis, as they aged. No alterations were found in organs other than the heart. <i>Sirt3</i> deficiency altered cardiac mitochondrial bioenergetics and caused hyperacetylation of optic atrophy 1 (OPA1), a SIRT3 target. These changes were associated with aberrant alignment of trans-mitochondrial cristae in cardiomyocytes, and cardiac dysfunction. Gene transfer of deacetylated <i>Opa1</i> restored cristae alignment in <i>Sirt3^-/-</i> mice, ameliorated cardiac reserve capacity, and protected the heart against hypertrophy and fibrosis. The translational relevance of these findings is in the data showing that <i>SIRT3</i> silencing in human-induced pluripotent stem cell-derived cardiomyocytes led to mitochondrial dysfunction and altered contractile phenotype, both rescued by <i>Opa1</i> gene transfer. <b><i>Innovation:</i></b> Our findings indicate that future approaches to heart failure could include SIRT3 as a plausible therapeutic target. <b><i>Conclusion:</i></b> SIRT3 has a major role in regulating mammalian life span. <i>Sirt3</i> deficiency leads to cardiac abnormalities, due to defective trans-mitochondrial cristae alignment and impaired mitochondrial bioenergetics. Correcting cardiac OPA1 hyperacetylation through gene transfer diminished heart failure in <i>Sirt3^-/-</i> mice during aging. <i>Antioxid. Redox Signal.</i> 31, 1255-1271.