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Sirt3 deficiency shortens lifespan and impairs cardiac mitochondrial function rescued by Opa1 gene transfer.

AIMS
Sirtuins, a family of NAD+-dependent deacetylases, are recognized as non-dispensable regulators of aging processes. Sirtuin 3 (SIRT3) is the main mitochondrial deacetylase that maintains mitochondrial bioenergetics, an essential prerequisite for healthy aging. Here using Sirt3 knock-out (Sirt3-/-) mice we sought to establish whether Sirt3 deficiency affected lifespan, an end-point that has never been tested formally in mammals, and uncover the mechanisms involved in organ damage associated with aging.


RESULTS
Sirt3-/- mice experienced a shorter lifespan 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. Sirt3 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 Opa1 restored cristae alignment in Sirt3-/- 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 SIRT3 silencing in human induced pluripotent stem cell-derived cardiomyocytes led to mitochondrial dysfunction and altered contractile phenotype, both rescued by Opa1 gene transfer.


INNOVATION
Our findings indicate that future approaches to heart failure could include SIRT3 as a plausible therapeutic target.


CONCLUSION
SIRT3 has a major role in regulating mammalian lifespan. Sirt3 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 Sirt3-/- mice during aging.