Knockdown of mitochondrial sirtuin sir-2.2 reduces alpha-synuclein clearance and impairs energy homeostasis in a model of ageing.

Mitochondria are the regulators of energy production and play a vital role in modulating ageing and age-associated diseases. We investigated the role of sirtuins, a well-studied class of longevity-associated proteins (NAD+-dependent histone deacetylases), in mitochondrial biology and Parkinson's disease pathology. In particular, we endeavoured to study the functional implications of the mitochondrial sirtuin sir-2.2 (orthologue of human SIRT4) in regulating neuroprotection in a Caenorhabditis elegans model of ageing. We observed that, upon sir-2.2 knockdown, alpha-synuclein aggregation was increased and expression of the dopamine transporter dat-1 was reduced. Also, the levels of markers of innate immunity, oxidative stress, mitophagy, mitochondrial unfolded protein response and autophagy were decreased, suggesting an important function of sir-2.2 in maintaining mitochondrial homeostasis, regulating protein clearance and ameliorating the disease condition. Because of their crucial role in regulating oxidative stress and mitochondrial quality control, studying mitochondrial sirtuins will provide therapeutic insights into the metabolic regulation of ageing and neurodegeneration.