• SBK3 is a mitochondrial-resident protein that is downregulated in pathological cardiac hypertrophy, and its overexpression protects against pressure overload-induced heart failure.
• Cardiac-specific SBK3 overexpression via AAV9-cTNT attenuates TAC-induced cardiac hypertrophy and dysfunction in mice.
• Mechanistically, SBK3 preserves mitochondrial ultrastructure, balances respiratory chain complexes, and modulates mitochondrial fission/fusion dynamics.
• SBK3 represents a novel mitochondrion-targeted therapeutic candidate for heart failure.