Mitochondrial Calcium Dysregulation and Targeted Therapies in Heart Failure

Heart failure (HF) is steadily increasing in prevalence and poses a major global health challenge, with substantial medical and economic burdens. HF represents the terminal stage of diverse cardiac disorders and is characterized by poor prognosis despite the availability of conventional pharmacological treatments, underscoring the urgent need for novel therapeutic approaches. Accumulating evidence highlights a strong association between HF and mitochondrial dysfunction, of which dysregulated mitochondrial calcium (mCa²⁺) homeostasis plays a pivotal role in disease pathogenesis. Ca²⁺ serves as an essential signaling messenger that regulates energy metabolism and also governs cell survival and myocardial contractility. Thus, this review introduces the mechanisms of mCa²⁺ uptake and efflux and the association of these processes with HF and emerging therapeutic strategies. We also discuss mCa²⁺ uniporter (MCU) inhibitors and Elamipretide, a mitochondria-targeted peptide. Collectively, this work provides novel insights and preclinical evidence supporting mitochondria-based interventions for HF.