UC San Diego

Myocardial aging is an independent risk factor for cardiovascular disease. Cardiac aging promotes adverse myocardial remodeling and the accumulation of poorly functioning senescent cells, leading to a decline in cardiac performance. Pathological remodeling is associated, in part, with changes occurring at the mitochondrial level exacerbating heart disease. Mitochondrial alteration during heart failure includes cellular changes in fuel utilization and alterations in mitochondrial dynamics, implicating mitochondrial biology as an important facet of cardiac aging biology. Pim kinases are protective in a cardiac context, in part by maintaining mitochondrial integrity. However, Pim protein expression diminishes during cardiac aging. Therefore, cardiac mitochondrial dynamics and metabolism were investigated in relationship to Pim kinases. The relationship between Pim1 and Dynamin Related Protein 1 (Drp1) was assessed as a novel mechanism to prevent Drp1 mediated fission. Drp1 mediates fission by mitochondrial localization during pathological challenge, sensitizing cardiomyocytes to apoptosis. Overexpressing Pim1 decreased total Drp1 levels, increased phosphorylation of Drp1 at serine 637, and inhibited Drp1 localization to mitochondria while preserving reticular morphology after simulated ischemia. Overexpression of Pim1 dominant negative (PDN) increased total mitochondrial Drp1, reduced phospho Drp1, and increased mitochondrial fragmentation. PDN hearts exhibit upregulation of BH3 only protein p53 upregulated modulator of apoptosis (PUMA) that mediates mitochondrial Drp1 accumulation and increased sensitivity to apoptotic stimuli. Therefore, Pim1 activity prevents Drp1 compartmentalization to the mitochondria and preserves reticular mitochondrial morphology. Cellular pathological hypertrophic remodeling and fetal gene program activation was evident in Pim Triple KnockOut (PTKO) mice phenotypic of cardiac aging. Cardiomyocyte senescence manifested by increased expression of cell cycle inhibitors and decreased telomere lengths. Changes in expression of PPAR[gamma] coactivator-1 (PGC-1) [alpha] and [Beta] led to alterations in mitochondrial ultrastructure and metabolism. An energy-starved phenotype was determined with decreased ATP and increased pAMPK:AMPK ratio, confirming changes in the PPAR signaling circuit. Overexpression of PGC-1[alpha] and c-Myc rescued changes in metabolism and restored energy homeostasis. These studies confirm the significant impact of Pim kinases on mitochondrial biology and support the notion to utilize Pim as a tool to prevent cardiac aging by preserving mitochondrial dynamics and metabolism