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Mitophagy Must Be Maintained at a Certain Level in Order to Provide Cardioprotection in Mice During Fasting
Author(s) -
Bantis Katrina,
Zhang Yawen,
Kobayashi Satoru,
Liang Qiangrong
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.580.3
Subject(s) - mitophagy , cardioprotection , parkin , mitochondrion , autophagy , medicine , endocrinology , ubiquitin ligase , cardiac function curve , genetically modified mouse , microbiology and biotechnology , biology , heart failure , ubiquitin , transgene , ischemia , biochemistry , apoptosis , disease , parkinson's disease , gene
Previous literatures have shown a clear yet undefined relationship between caloric restriction, or fasting, and preserved cardiac function. Indeed, it has been demonstrated that fasting attenuates acute ischemic injury, chronic cardiac remodeling, and heart failure in mammalian models. Mitophagy, or mitochondrial degradation, has been implicated in mediating such cardioprotection, however the underlying molecular mechanism remains uncharacterized. Mitophagy plays a homeostatic role in mammalian cells, targeting excessive or damaged mitochondria for lysosomal degradation. Such degradation is essential in both dictating mitochondrial turnover during a cell's basal state as well as during times of stress when oxygen free radical species threaten a cell's ability to appropriately perform. We previously showed that one‐day fasting accelerated while two‐day fasting reduced mitophagy flux in the mouse heart, suggesting time‐differential effects of fasting on cardiac mitophagy. In the present study, we set out to determine if manipulating the level of mitophagy could mediate cardiac function during fasting. We subjected genetically altered transgenic (TG) mice with moderate‐ and high‐expression levels of Parkin, an E3 ubiquitin ligase that tags damaged mitochondria for degradation in order to promote mitophagy, in the heart as well as Parkin knockout (KO) mice and wild‐type (WT) mice to 48‐hours of complete caloric restriction. We then determined their cardiac function using echocardiography and invasive left ventricular (LV) catheterization. The results showed that 48‐hour fasting triggered cardiac dysfunction in WT mice, as indicated by significantly reduced heart rate, fractional shortening, maximal left ventricular pressure, and left ventricular contractility. Moreover, between the WT control (fed) and fasted KO mice, the latter group showed a significant reduction in these same cardiac parameters, suggesting that mitophagy is essential to the maintenance of cardiac function during fasting. Interestingly, between the WT control and the fasted TG mice which expressed moderate levels of Parkin, a significant change in cardiac function was not observed whereas significant cardiac dysfunction was observed between the WT control and TG mice that expressed high levels of Parkin. Taken collectively, our findings suggest that the downregulation of mitophagy under prolonged fasting mediates cardiac dysfunction and, thus, a specific level of mitophagy is required in order to be cardioprotective in mice. Support or Funding Information This study was supported by an NIH grant. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .