Physician Kaohsiung Medical University Kaohsiung, Taiwan
Abstract: Metabolic syndrome, characterized by abnormal lipid metabolism and elevated cardiovascular risk, involves lipoprotein abnormalities that may impair mitochondrial function and contribute to mitochondrial-related diseases. Among these, very-low-density lipoproteins (VLDL) are implicated in mitochondrial dysfunction, though the underlying mechanisms remain unclear. This study aimed to elucidate the effects of VLDL on cardiomyocyte mitochondria using human induced pluripotent stem cell-derived cardiomyocytes (iCMs). Differentiation of iCMs from mesodermal induction to progenitor formation was confirmed, and VLDL-induced lipotoxicity was investigated through assessments of intracellular ROS and Ca²⁺ handling dysfunction. RNA sequencing revealed 27 upregulated and 97 downregulated differentially expressed genes (DEGs) associated with VLDL exposure, highlighting significant pathways linked to mitochondrial impairment. KEGG pathway mapping pointed to SIRT1-associated mechanisms as a critical contributor to VLDL-induced mitochondrial dysfunction. Functional assays, including Seahorse analysis, demonstrated a 23–36% reduction in mitochondrial oxygen consumption rates (OCR) following VLDL exposure, confirming its adverse impact on mitochondrial respiration. Immunofluorescence further indicated intra-mitochondrial modifications linked to VLDL lipotoxicity. Together, these findings provide new insights into the role of VLDL in disrupting mitochondrial function and metabolism in cardiomyocytes, offering mechanistic explanations for the progression of cardiovascular disease in patients with metabolic syndrome.
