KLF9 Is A Key Mediator Of Heart Mitochondrial Function

Mitochondrial homeostasis is critical for tissue health,and mitochondrial dysfunction contributes to numerous diseases,including heart failure.Adult mice with heart conditionally KLF9 ablating developed heart dysfunction with or without pressure overload,and marked alteration in mitochondrial shape,size and alignment.Further,KLF9 ablating resulted impaired mitochondrial biogenesis.We determined that KLF9 binds to PGC-la and transcriptional regulate metabolic and mitochondrial genes.We also uncovered distinct effects on mitophagy of ablation versus overexpression of KLF9.Conditionally KLF9 ablating caused inhibition of mitophagy with eccentric remodeling and no cardiomyocyte dropout.However,conditionally KLF9 overexpressing evoked mitochondrial enlargement,lethal dilated cardiomyopathy,and cardiomyocyte necrosis.Parallel studies in cultured murine embryonic fibroblasts(MEFs)and in vivo mouse hearts revealed that KLF9 deletion provoked accumulation of defective mitochondrial exhibiting an unfolded protein response,without appropriately increasing mitophagy.Conversely,KLF 9 overexpression increased mitophagy,and caused a generalized loss of mitochondria.Mitochondrial permeability transition pore(MPTP)opening in KLF9 TG mitochondria was associated with mitophagy and contributed to cardiomyocyte necrosis and dilated cardiomyopathy in mice.KLF9,MPTP,and cardiomyocyte mitophagy are functionally integrated.KLF9 ablation and overexpression have different roles during cardiac mitochondrial quality control in vivo.Collectively,these findings identify KLF9 as a nodal transcriptional regulator of mitochondrial homeostasis.