This review provides a holistic perspective on the bi-directional relationship between cardiac mitochondrial dysfunction and myocardial structural remodeling in the context of metabolic heart disease, natural cardiac aging, and heart failure. First, a review of the physiologic and molecular drivers of cardiac mitochondrial dysfunction across a range of increasingly prevalent conditions such as metabolic syndrome and cardiac aging is presented, followed by a general review of the mechanisms of mitochondrial quality control (QC) in the heart. Several important mechanisms by which cardiac mitochondrial dysfunction triggers or contributes to structural remodeling of the heart are discussed: accumulated metabolic byproducts, oxidative damage, impaired mitochondrial QC, and mitochondrial-mediated cell death identified as substantial mechanistic contributors to cardiac structural remodeling such as hypertrophy and myocardial fibrosis. Subsequently, the less studied but nevertheless important reverse relationship is explored: the mechanisms by which cardiac structural remodeling feeds back to further alter mitochondrial bioenergetic function. We then provide a condensed pathogenesis of several increasingly important clinical conditions in which these relationships are central: diabetic cardiomyopathy, age-associated declines in cardiac function, and the progression to heart failure, with or without preserved ejection fraction. Finally, we identify promising therapeutic opportunities targeting mitochondrial function in these conditions.

Sequestosome1 (p62) is a multifunctional signaling molecule and an autophagy adaptor protein. Previous work demonstrated that mice with whole-body p62 knockout recapitulated many detrimental features of aging. Of note, these mice developed late onset obesity and systemic abnormalities that could have contributed to their aging phenotype. Multiple studies have also shown that cardiac dysfunction can be linked to an increase in oxidative stress. The Nrf2-Keap1 pathway is critical for protection against oxidative stress and p62 has been shown to interact with Keap1, thus allowing Nrf2 activation to induce anti-oxidant responses. However, the role of p62 in the heart is not well known. We tested the hypothesis that p62 plays an important homeostatic role in the heart through the regulation of redox homeostasis via the Nrf2-Keap1 pathway. Wild-type and cardiomyocytes-specific p62 knockout (cp62 KO) mice at 8 weeks and 60 weeks of age were used. At 8 weeks, cp62KO mice exhibited mild but significant contractile dysfunction compared to the wild-type controls. By 60 weeks, the KO mice developed cardiac hypertrophy, fibrosis and increased oxidative stress. cp62 KO hearts had decreased Nrf2 nuclear translocation and activation as evidenced by a 50% (p<0.005) reduction in the expression of the Nrf2 target glutathione S-transferase A4 ( Gsta2 ) gene. These findings were further validated by transcriptomic analysis followed by KEGG pathway analysis, which indicated that redox pathways were altered in the 60-week p62 null hearts. To examine the mechanisms involved in p62 regulation of Nrf2-Keap signaling, we utilized rat cardiac H9c2 myoblasts. Loss of p62 using p62 siRNA in H9c2 cells resulted in decreased Nrf2 levels and increased oxidative stress. These pathological consequences of suppressing p62 could be attributed to increased Nrf2 degradation via the proteasome. Together, these results reveal a previously uncharacterized role for p62 in the maintenance of cardiac redox signaling in the mouse heart.

Despite recent medical advances, heart failure (HF) remains to be the leading cause of mortality worldwide. Delineating the underlying molecular mechanisms involved in the pathogenesis of HF is critical for the development of new therapies. The transcription factor PRDM16 is involved in cell fate determination and differentiation. We previously showed that PRDM16 variants/deletion resulted in left ventricular non-compaction cardiomyopathy in humans and mice indicating its involvement in cardiac development. Here, we investigated the role of PRDM16 in adult cardiac physiology. We showed that patients with HF exhibited a significant reduction in cardiac PRDM16 mRNA expression compared to control individuals. These results were substantiated by the significant attenuation of Prdm16 mRNA 2 weeks post- transverse aortic constriction (TAC) in mice when compared to age matched sham controls. Additionally, cultured neonatal rat ventricular cardiomyocytes treated with the hypertrophy inducing agent, phenylephrine, demonstrated a suppression of Prdm16 gene expression while fibrotic gene expression was elevated. To directly assess the contribution of PRDM16 to cardiac hypertrophy and HF, we generated mice with tamoxifen-inducible cardiomyocyte-specific Prdm16 deletion (CiPrdm16). CiPrdm16 KO mice developed concentric hypertrophy as evidenced by enhanced heart weight/tibia length, elevated left ventricular mass and increased cardiomyocyte hypertrophy. Initially, ciPrdm16 KO mice exhibited enhanced contractility but progressively developed contractile dysfunction and impaired diastolic function. Consistent with these findings, transcriptomic analysis revealed an increase in protein synthesis pathways in ciPrdm16 KO hearts compared to wild-type controls. Collectively, these data show for the first time that PRDM16 transcriptionally regulates pro-hypertrophic signaling in the adult mouse heart and may contribute to the progression of HF in humans.