Mitochondria are the central regulators of myocardial metabolism and are responsible for maintaining metabolic homeostasis across a wide range of cardiac workloads. The molecular mechanisms that regulate mitochondrial function are gradually being uncovered, but the critical link between mitochondrial morphology and oxidative capacity is unknown. Mitofusin (Mfn) 1 and 2 are two recently-discovered mitochondrial-shaping proteins that are found on the outer membrane and are major regulators of mitochondrial architecture. Recent evidence from our laboratory suggests that cardiac myocyte-specific ablation of both Mfn1 and Mfn2 leads to a greater number of fragmented mitochondria, left ventricular remodeling and systolic dysfunction, and increased mortality during the transition from fetal to post-natal life. Concomitant with changes in mitochondrial and cardiac morphology was decreased expression of nuclear and mitochondrial transcription factors which collectively play a critical role in mitochondrial biogenesis. These findings suggest that mitofusins likely participate in the heart's adaptive metabolic response to increased energetic demand. To address this possibility, we will, for the first time, examine the role of mitofusins in the development of pathological and physiological cardiac hypertrophy and characterize the differential effects of Mfn1 and/or Mfn2 ablation in the adult cardiac myocyte. We will employ an extensive mouse genetic toolkit containing mitofusin conditional single and double knockouts, as well as mice with three of four mitofusin alleles deleted (monoallelics). These mice will be used to investigate mitofusins in post-natal cardiac growth and to explore mechanisms by which mitochondrial morphology affects mitochondrial content and respiratory function. These experiments will provide a comprehensive top-down analysis of mitofusin function in the adult mammalian myocardium, linking the intact heart phenotype, isolated cardiac myocyte physiology, and mitochondrial respiration and dynamics.

Public Health Relevance

In the heart, organelles referred to as mitochondria have a critical role in balancing energy production with cellular energetic demand. It is now recognized that mitochondria are dynamic structures that undergo continuous fission and fusion, the latter being regulated by proteins called mitofusins. Using mice with heart- restricted mitofusin deletion, we will examine the importance of these proteins in pathological and physiological cardiac growth and in regulating heart muscle cell physiology.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
4R01HL120160-04
Application #
9066192
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Schwartz, Lisa
Project Start
2013-09-01
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
Wu, Chia-Ling; Satomi, Yoshinori; Walsh, Kenneth (2017) RNA-seq and metabolomic analyses of Akt1-mediated muscle growth reveals regulation of regenerative pathways and changes in the muscle secretome. BMC Genomics 18:181
Karki, Shakun; Ngo, Doan T M; Farb, Melissa G et al. (2017) WNT5A regulates adipose tissue angiogenesis via antiangiogenic VEGF-A165b in obese humans. Am J Physiol Heart Circ Physiol 313:H200-H206
Zuriaga, Maria A; Fuster, Jose J; Gokce, Noyan et al. (2017) Humans and Mice Display Opposing Patterns of ""Browning"" Gene Expression in Visceral and Subcutaneous White Adipose Tissue Depots. Front Cardiovasc Med 4:27
MacLauchlan, Susan; Zuriaga, Maria A; Fuster, José J et al. (2017) Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis. Arthritis Res Ther 19:166
Maruyama, Sonomi; Nakamura, Kazuto; Papanicolaou, Kyriakos N et al. (2016) Follistatin-like 1 promotes cardiac fibroblast activation and protects the heart from rupture. EMBO Mol Med 8:949-66
Nakamura, Kazuto; Sano, Soichi; Fuster, José J et al. (2016) Secreted Frizzled-related Protein 5 Diminishes Cardiac Inflammation and Protects the Heart from Ischemia/Reperfusion Injury. J Biol Chem 291:2566-75
Lee, Richard T; Walsh, Kenneth (2016) The Future of Cardiovascular Regenerative Medicine. Circulation 133:2618-25
Farb, Melissa G; Karki, Shakun; Park, Song-Young et al. (2016) WNT5A-JNK regulation of vascular insulin resistance in human obesity. Vasc Med 21:489-496
Clark, Amanda L; Maruyama, Sonomi; Sano, Soichi et al. (2016) miR-410 and miR-495 Are Dynamically Regulated in Diverse Cardiomyopathies and Their Inhibition Attenuates Pathological Hypertrophy. PLoS One 11:e0151515
Fuster, José J; Zuriaga, María A; Ngo, Doan Thi-Minh et al. (2015) Noncanonical Wnt signaling promotes obesity-induced adipose tissue inflammation and metabolic dysfunction independent of adipose tissue expansion. Diabetes 64:1235-48

Showing the most recent 10 out of 22 publications