Project Details

Description

The mechanisms underlying cardiac myocyte demise and heart failure remain a central focus of much of the research in the field. Not surprising, dysfunction and damage of the mitochondria are major causes of cell death, as they are the main source of energy in the cell. For that same reason, they are also subject to several self-preserving and quality control mechanisms during stress. One of the understudied aspects of this research include the mechanisms via which mitochondria can promptly increase energy supply upon an increase in demand, during health or disease, and the role of the reserve respiratory capacity (RRC) in this process, its source, and mechanisms of regulation. In our recent report and preliminary data, we have identified multiple factors and conditions that modulate the levels of the RRC, including growth factors, and the AMPK-Sirt3 axis. We also reported that mitochondrial complex II (cII), composed of succinate dehydrogenase (Sdh) subunits a,b,c,d, is the main source of the RRC in cardiac myocytes (Fig. 1). Notably, we found that during heart failure cII activity and RRC are significantly reduced, which is associated with reduced expression of Sdh assembly factor 1 (Sdhaf1; mutated in infantile mitochondrial disease). We could rescue this effect via expression of an acetylation- and degradation-resistant, Sdhaf1 mutant. On the other hand, partial knockdown of this gene in the heart in vivo results in abrogation of RRC, accelerates myocyte death, and cardiac dysfunction. We hypothesize that: 1) The RRC is a product of cII assembly and activity, which is regulated by Sdhaf1. Upstream regulators of this factor and RRC include sensors and regulators of cellular energy such as AMPK and Sirt3. Regulation of Sdhaf1 is mediated through both long-term transcriptional changes and acute posttranslational modifications. 2) The RRC supports myocyte survival during stress conditions, mainly via increasing energy production during increased demand, and reducing the production of reactive oxygen species through preventing the disassembly of cII, 3) During cardiac hypertrophy Sdhaf1 is downregulated, which contributes to disassembly of cII, myocyte loss, and failure. Therefore, replenishing the heart with an acetylation- and degradation-resistant Sdhaf1 will help improve myocyte health and survival during stress. The specific aims are: 1) Study the mechanisms that contribute to the development and regulation of mitochondrial reserve respiratory capacity, with a focus on the role of complex II and its regulation via Sdhaf1 and AMPK- Sirt3. 2) Study the mechanisms via which the mitochondrial reserve respiratory capacity influences cell survival and resistance to cell death, with a focus on the assembly/disassembly of complex II, and its contribution to ATP and ROS production. 3) Determine if reconstituting Sdhaf1 and Sirt3 in the heart during hypertrophy could restore assembly and activity of cII, and the reserve respiratory capacity, and their roles in enhancing myocyte survival and slowing the progression of heart failure.
StatusActive
Effective start/end date7/1/176/30/21

Funding

  • National Institutes of Health: $397,500.00
  • National Institutes of Health: $397,500.00
  • National Institutes of Health: $397,500.00

ASJC

  • Medicine(all)

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