Project Details
Description
Summary
Mitochondria are central intracellular organelles that mediate metabolism and ATP production. In order to
maintain the function of mitochondria during stress, cardiomyocytes (CMs) have multiple layers of quality
control mechanisms mediating mitochondrial fission/fusion, degradation and biogenesis. Mitophagy, a
mitochondria-selective form of autophagy, is a major mechanism of degradation of damaged mitochondria and
protects the heart against heart failure. In general, mitophagy is induced by the same molecular mechanisms
commonly used by general autophagy, including “autophagy-related” (Atg) molecules, and additional
molecules, including Pink1/Parkin. However, increasing lines of evidence suggest that mitophagy is also
induced independently of conventional autophagy. During the past funding cycle, we have shown that an
unconventional form of mitophagy plays a more critical role in protecting the heart during ischemia than the
conventional form of mitophagy. This unconventional form of mitophagy, called alternative mitophagy, utilizes
molecular machinery distinct from that used by conventional mitophagy, namely the Ulk1-Rab9-Rip1-Drp1
protein complex. Currently, the functional significance and the molecular mechanisms of alternative mitophagy
remain poorly understood. Our long-term goal is to demonstrate the functional significance of alternative
mitophagy in the heart during chronic and more pathologically relevant conditions in vivo, elucidate the
underlying molecular mechanisms, and eventually apply our knowledge to treat heart disease by stimulating
alternative mitophagy. Interestingly, although conventional autophagy and mitophagy are activated in response
to high fat diet (HFD) consumption in the mouse model of diabetic cardiomyopathy, their activation is transient
and they protect the heart only during the early phase of HFD consumption. On the other hand, an
unconventional form of mitophagy is activated in a more prolonged manner and appears to play an essential
role in protecting the heart during the chronic phase of HFD consumption. We here hypothesize that
alternative mitophagy is the predominant form of mitophagy in the heart during the chronic phase of
HFD consumption and plays an essential role in protecting the heart against diabetic cardiomyopathy.
Alternative mitophagy is activated through a TFE3-dependent transcriptional program and the direct
association of a large protein complex, containing Drp1 and Drp1 interacting proteins, with
mitochondria. We will test our hypothesis using unique indicators of mitophagy, genetically altered mouse
models, morphological analyses, including immunogold analyses, lipidomics, transcriptome analyses, and
ChIP-sequencing analyses. Our study will demonstrate a novel and targetable mitochondrial quality control
mechanism during the chronic development of diabetic cardiomyopathy. Our study should lead to the
development of novel interventions to maintain the quality of mitochondria in diabetic patients and alleviate
their cardiac complications, including cardiac hypertrophy/dysfunction, lipotoxicity, and inflammation.
Status | Active |
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Effective start/end date | 8/15/17 → 6/30/25 |
Funding
- National Heart, Lung, and Blood Institute: $600,995.00
- National Heart, Lung, and Blood Institute: $571,543.00
- National Heart, Lung, and Blood Institute: $600,995.00
- National Heart, Lung, and Blood Institute: $600,995.00
- National Heart, Lung, and Blood Institute: $560,113.00
- National Heart, Lung, and Blood Institute: $600,995.00
- National Heart, Lung, and Blood Institute: $571,543.00
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