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However, the molecular mechanisms regulating these interactions during ischemia are not fully understood. We found that HR significantly decreased cardiomyocyte expression and phosphorylation of Rab8a, a small GTPase that interacts with the LD\u2010associated protein perilipin 5 to mediate LD\u2013mitochondria tethering. Using long\u2010chain fatty acid\u00a0(LCFA) tracking assays we confirmed that loss of Rab8a disrupted physical contact between these organelles to impair the transfer of LCFA from LDs to mitochondria. Furthermore, HR led to the accumulation of intracellular lipids via a combination of both lipolysis and lipophagy, resulting in metabolic stress. To counteract this defect, we evaluated the therapeutic potential of ALY688, a peptide agonist of adiponectin receptors known to stimulate the AMPK\u2013Rab8a signaling axis. Our data indicated that treatment with ALY688 preserved Rab8a expression during HR, thereby maintaining LD\u2013mitochondria interactions and improving metabolic function. These findings uncover a novel Rab8a\u2010dependent mechanism regulating lipid metabolism under ischemic\/hypoxic stress and highlight the potential of adiponectin mimetics like ALY688 to mitigate metabolic dysfunction in ischemic heart disease.<\/jats:p>","DOI":"10.1002\/mco2.70845","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T06:42:06Z","timestamp":1786084926000},"source":"Crossref","is-referenced-by-count":0,"title":["Loss of Rab8a\u2010Dependent Tethering of Lipid Droplets to Mitochondria Contributes to Hypoxia\u2013Reoxygenation Injury"],"prefix":"10.1002","volume":"7","author":[{"given":"Jialing","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Biology, Faculty of Science York University  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Joyce","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Microbiology and Immunology, Faculty of 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