SBK2-Driven NDUFV1 Phosphorylation and Translocation Limits Cardiac Hypertrophy

Area of Science:

• Cardiovascular Biology
• Mitochondrial Medicine
• Molecular Cardiology

Background:

• Heart failure is a major health burden, often driven by pathological cardiac hypertrophy.
• Mitochondrial dysfunction, specifically impaired mitochondrial complex I activity, is critical in disease progression.
• Regulatory mechanisms of mitochondrial dysfunction in heart failure are not well understood.

Purpose of the Study:

• To investigate the role of Src homology 3 domain-binding kinase 2 (SBK2) in cardiac hypertrophy.
• To determine if SBK2 modulates mitochondrial complex I function in the context of heart failure.
• To elucidate the molecular mechanisms by which SBK2 influences cardiac function.

Main Methods:

• Cross-species transcriptomic screening and UK Biobank analyses identified SBK2 as a potential risk factor.
• Loss- and gain-of-function studies in cardiomyocytes and mice were performed.
• Proteomic, interactome, and biochemical analyses identified SBK2 substrates and downstream effects on mitochondrial function.

Main Results:

• SBK2 expression was reduced in hypertrophic hearts; SBK2 overexpression attenuated hypertrophy and fibrosis.
• SBK2 directly phosphorylates NDUFV1 (NADH: ubiquinone oxidoreductase core subunit V1) at serine 251, enhancing its mitochondrial import.
• This phosphorylation promotes mitochondrial complex I activity, respiratory supercomplex assembly, and overall mitochondrial health, protecting against hypertrophy.

Conclusions:

• SBK2 acts as an upstream kinase, linking cytosolic signaling to mitochondrial protein import and function.
• The SBK2-NDUFV1 axis sustains complex I integrity and mitochondrial function, restraining pathological cardiac hypertrophy.
• This pathway represents a novel therapeutic target for heart failure and related conditions.