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Novel mechanisms linking metabolic signaling and mitochondria to the pathophysiology of heart failure

E.D. Abel, FOE Diabetes Research Center and Division of Endocrinology and Metabolism, University of Iowa, Carver College of Medicine, 169 Newton Rd, 4312 PBDB, Iowa City, IA 52242, USA.

It is widely accepted that heart failure of diverse etiologies is associated with impaired mitochondrial bioenergetics (Doenst, Nguyen & Abel, 2013). However, recent evidence suggests that the relationship between mitochondrial dysfunction and heart failure extends beyond reduced ATP or high-energy phosphate generation. For example, heart failure is associated with reduced expression of the transcriptional co-activator PPAR gamma co-activator 1 alpha (PGC-1α), which is believed to account in part for the impairment in mitochondrial oxidative capacity that occurs in the failing heart (Riehle & Abel ED, 2012). Indeed mice, when mice with reduced expression of PGC-1α or PGC-1β are subjected to transverse aortic constriction, the transition to heart failure is rapidly accelerated (Arany et al., 2006; Riehle et al., 2011). However, when PGC-1α is sustained and mitochondrial bioenergetics preserved, heart failure was not ameliorated (Pereira et al., 2014). Interestingly, in mice with inducible transgenic overexpression of the glucose transporter GLUT1, increasing glycolysis and utilization was associated with preservation of mitochondrial bioenergetics and attenuation of LV remodeling (Pereira et al., 2013). Thus, the metabolic mechanisms linking mitochondrial dysfunction with heart failure likely transcends bioenergetics and ATP generation, but also includes novel signaling pathways that are regulated by metabolic intermediates (Karlstaedt et al., 2016; Lee et al., 2016; Nabeebaccus et al., 2017) and may contribute to left ventricular remodeling.

Arany Z, Novikov M, Chin S, Ma Y, Rosenzweig A, Spiegelman BM. (2006). Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-γ coactivator 1α. Proc Natl Acad Sci USA 103, 10086-91.

Doenst T, Nguyen TD, Abel ED. (2013) Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res 113, 709-24.

Karlstaedt A, Zhang X, Vitrac H, Harmancey R, Vasquez H, Wang JH, Goodell MA, Taegtmeyer H. (2016). Oncometabolite d-2-hydroxyglutarate impairs α-ketoglutarate dehydrogenase and contractile function in rodent heart. Proc Natl Acad Sci USA 113, 10436-41.

Lee CF, Chavez JD, Garcia-Menendez L, Choi Y, Roe ND, Chiao YA, Edgar JS, Goo YA, Goodlett DR, Bruce JE, Tian R. (2016). Normalization of NAD+ redox balance as a therapy for heart failure. Circulation 134, 883-94.

Nabeebaccus AA, Zoccarato A, Hafstad AD, Santos CX, Aasum E, Brewer AC, Zhang M, Beretta M, Yin X, West JA, Schroder K, Griffin JL, Eykyn TR, Abel ED, Mayr M, Shah AM. (2017). Nox4 reprograms cardiac substrate metabolism via protein O-GlcNAcylation to enhance stress adaptation. JCI Insight. 2(24): e96184. doi: 10.1172/jci.insight.96184

Pereira RO, Wende AR, Olsen C, Soto J, Rawlings T, Zhu Y, Anderson SM, Abel ED. (2013) Inducible overexpression of GLUT1 prevents mitochondrial dysfunction and attenuates structural remodeling in pressure overload but does not prevent left ventricular dysfunction. J Am Heart Assoc 2:e000301. doi: 10.1161/JAHA.113.000301

Pereira RO, Wende AR, Crum A, Hunter D, Olsen CD, Rawlings T, Riehle C, Ward WF, Abel ED. (2014). Maintaining PGC-1α expression following pressure overload-induced cardiac hypertrophy preserves angiogenesis but not contractile or mitochondrial function. FASEB J 28, 3691-702.

Riehle C, Abel ED. (2012) PGC-1 proteins and heart failure. Trends Cardiovasc Med 22, 98-105.

Riehle C, Wende AR, Zaha VG, Pires KM, Wayment B, Olsen C, Bugger H, Buchanan J, Wang X, Moreira AB, Doenst T, Medina-Gomez G, Litwin SE, Lelliott CJ, Vidal-Puig A, Abel ED. (2011). PGC-1beta deficiency accelerates the transition to heart failure in pressure overload hypertrophy. Circ Res 109, 783-93.