OBJECTIVES: To investigate the effect and mechanism of sirtuin5 (SIRT5) on mitochondrial dysfunction and cardiac hypertrophy induced by receptor-interacting protein 140 (RIP140). MATERIALS AND METHODS: The neonatal rat cardiomyocytes (NRCMs) and SD rats were treated with Angiotensin II (Ang II) to induce RESULTS: The expression of SIRT5 was down-regulated in NRCMs and hearts treated with Ang II. Overexpression of SIRT5 protected cardiomyocytes from AngII-induced hypertrophy, whereas knockdown of SIRT5 resulted in cardiac hypertrophy. Moreover, since SIRT5 was regulated by the transcriptional coactivator, we also found that SIRT5 could be negatively regulated by the transcriptional corepressor RIP140 in cardiomyocytes. Furthermore, SIRT5 significantly attenuated energy metabolic dysregulation and mitochondrial dysfunction and exerted its protective role on myocardial hypertrophy under the regulation of RIP140. CONCLUSION: SIRT5 exerts a protective role in mitochondrial dysfunction and cardiac hypertrophy induced by RIP140.