Purpose Mitochondrial dysfunction plays a vital role in the pathophysiologic process of heart failure (HF). As a quality control system, mitochondrial fusion and fission are under control of mitochondrial fusion and fission-related proteins. The objective of this study was to investigate the effects of common variants in mitochondrial fusion and fission-related genes on the prognosis of HF. Methods We performed whole exome sequencing (WES) with 1000 HF patients; the statistically significant variant was further genotyped in the replicated population with 2324 HF patients. A series of function analysis including western blot, cell proliferation assay, and in vitro OMA1 activity assay were conducted to illuminate the underlying mechanism. Results We identified a missense variant rs17117699 associated with the prognosis of HF in group without beta-blocker use rather than with beta-blocker use in two-stage population: adjusted P = 0.79, HR = 0.88 (0.36-2.13) in group with beta-blocker use and adjusted P = 0.016, HR = 1.43 (1.07-1.91) in group without beta-blocker in first-stage population; adjusted P = 0.42, HR = 0.85 (0.56-1.28) in group with beta-blocker use and adjusted P = 0.015, HR = 1.39 (1.06-1.82) in group without beta-blocker in replicated stage. Functional analysis indicated that rs17117699-G allele increased the activity of OMA1 assessed by the ratio of S-OPA1 to L-OPA1 and suppressed cells proliferation under ISO treatment when compared with rs17117699-T allele. Furthermore, OMA1 functioned downstream of beta-adrenergic receptor signaling and ISO-induced OPA1 cleavage is dependent on OMA1. Conclusions Our findings demonstrate that rs17117699T>G in OMA1 increases the risk of HF mortality via enhancing its OPA1 cleavage activity. It is a promising potential treatment target for HF.