Szulik 2023 Basic Res Cardiol

Szulik MW, Valdez S, Walsh M, Davis K, Bia R, Horiuchi E, O'Very S, Laxman AK, Sandaklie-Nicolova L, Eberhardt DR, Durrant JR, Sheikh H, Hickenlooper S, Creed M, Brady C, Miller M, Wang L, Garcia-Llana J, Tracy C, Drakos SG, Funai K, Chaudhuri D, Boudina S, Franklin S (2023) SMYD1a protects the heart from ischemic injury by regulating OPA1-mediated cristae remodeling and supercomplex formation. https://doi.org/10.1007/s00395-023-00991-6

» Basic Res Cardiol 118:20. PMID: 37212935 Open Access

Szulik MW, Valdez S, Walsh M, Davis K, Bia R, Horiuchi E, O'Very S, Laxman AK, Sandaklie-Nicolova L, Eberhardt DR, Durrant JR, Sheikh H, Hickenlooper S, Creed M, Brady C, Miller M, Wang L, Garcia-Llana J, Tracy C, Drakos SG, Funai K, Chaudhuri D, Boudina S, Franklin S (2023) Basic Res Cardiol

Abstract: SMYD1, a striated muscle-specific lysine methyltransferase, was originally shown to play a key role in embryonic cardiac development but more recently we demonstrated that loss of Smyd1 in the murine adult heart leads to cardiac hypertrophy and failure. However, the effects of SMYD1 overexpression in the heart and its molecular function in the cardiomyocyte in response to ischemic stress are unknown. In this study, we show that inducible, cardiomyocyte-specific overexpression of SMYD1a in mice protects the heart from ischemic injury as seen by a > 50% reduction in infarct size and decreased myocyte cell death. We also demonstrate that attenuated pathological remodeling is a result of enhanced mitochondrial respiration efficiency, which is driven by increased mitochondrial cristae formation and stabilization of respiratory chain supercomplexes within the cristae. These morphological changes occur concomitant with increased OPA1 expression, a known driver of cristae morphology and supercomplex formation. Together, these analyses identify OPA1 as a novel downstream target of SMYD1a whereby cardiomyocytes upregulate energy efficiency to dynamically adapt to the energy demands of the cell. In addition, these findings highlight a new epigenetic mechanism by which SMYD1a regulates mitochondrial energetics and functions to protect the heart from ischemic injury. • Keywords: Cristae, Ischemic heart failure, Methyltransferase, Mitochondrial respiration, SMYD1 • Bioblast editor: Plangger M

Labels: MiParea: Respiration, Genetic knockout;overexpression  Pathology: Cardiovascular 

Organism: Mouse  Tissue;cell: Heart  Preparation: Isolated mitochondria 

Coupling state: LEAK, OXPHOS, ET  Pathway: N, NS  HRR: Oxygraph-2k 

2023-05