{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T06:26:02Z","timestamp":1791699962762,"version":"4.3.4"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Cardiac aging involves progressive mitochondrial dysfunction, contributing to heart failure. Cardiolipin (CL), essential for mitochondrial function, is increasingly depleted in aging cardiomyocytes, promoting mitochondrial decline. Lysosomal degradation relies on v-ATPase (vacuolar-type H+-ATPase)\u2013mediated acidification, and although lysosomes regulate phospholipid metabolism, their roles in CL homeostasis during aging remains unclear. This study examines whether v-ATPase dysfunction drives age-related cardiac changes by disrupting CL metabolism and mitochondrial function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      To investigate underlying mechanisms and causality, we use RNA sequencing, targeted lipidomics, immunofluorescence microscopy, co-immunoprecipitation, proximity ligation assays, subcellular fractionation, mitochondrial respiration analysis and echocardiography, a cardiolipin synthase-1 (\n                      <jats:italic toggle=\"yes\">Crsl1<\/jats:italic>\n                      ) knockout mouse model, and 2 v-ATPase knockout models. In addition, we assess whether a nutraceutical intervention targeting v-ATPase dysfunction can mitigate heart failure in aging mouse models and elderly people.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>Our present findings reveal a sequence of events driving age-related cardiomyopathy: declining cardiac nicotinamide adenine dinucleotide levels impair v-ATPase\u2013mediated lysosomal acidification by weakening the interaction between nicotinamide adenine dinucleotide\u2013dependent glycolytic enzyme aldolase and v-ATPase. This disruption increases lysosomal membrane permeability by reducing lysosomal acidification, allowing cathepsin B to leak into mitochondria. There, cathepsin B disrupts mitochondrial CRLS1 (cardiolipin synthase I), impairing CL synthesis and remodeling. The resulting CL deficiency causes mitochondrial oxidative stress and programmed cell death, leading to mitochondrial and cardiac dysfunction. Genetic or chemical inhibition of v-ATPase and of CRLS1 in mouse models reproduce these age-related defects, highlighting their central roles in cardiac aging. Restoring nicotinamide adenine dinucleotide levels rescues lysosomal acidification and CL metabolism, protecting against age-related cardiomyopathy in rodents and humans.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Augmenting v-ATPase\u2013mediated lysosomal acidification offers novel therapeutic strategies to combat age-related cardiomyopathy by rewiring CL homeostasis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.078376","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T09:00:19Z","timestamp":1781686819000},"page":"835-858","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Vacuolar H\n                    <sup>+<\/sup>\n                    -ATPase Preserves Cardiolipin Homeostasis Through the Lysosomal-Mitochondrial Axis to Restrain Cardiac Aging"],"prefix":"10.1161","volume":"154","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1058-6407","authenticated-orcid":true,"given":"Hongtao","family":"Tie","sequence":"first","affiliation":[{"name":"Department of Cardiothoracic Surgery, First Affiliated Hospital of Chongqing Medical University, Center for Obesity and Metabolic Diseases Research, School of Basic Medical Sciences (H.T., M.H., X.L., S.W.), Chongqing Medical University, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqian","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, First Affiliated Hospital of Chongqing Medical University, Center for Obesity and Metabolic Diseases Research, School of Basic Medical Sciences (H.T., M.H., X.L., S.W.), Chongqing Medical University, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9986-5201","authenticated-orcid":true,"given":"Yumeng","family":"Li","sequence":"additional","affiliation":[{"name":"Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences (Y.L., X.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8419-9357","authenticated-orcid":true,"given":"Min","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Upper Airway Inflammation and Tumor Laboratory, First Affiliated Hospital of Chongqing Medical University, China (M.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4316-684X","authenticated-orcid":true,"given":"Dietbert","family":"Neumann","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht School for Cardiovascular Diseases, Maastricht, The Netherlands (D.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruimin","family":"Liu","sequence":"additional","affiliation":[{"name":"Maternal-Fetal Medicine Center in Fetal Heart Disease, Capital Medical University, Beijing Anzhen Hospital, China (R.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5843-8705","authenticated-orcid":true,"given":"Jun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine (J.Z.), Chongqing Medical University, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0234-438X","authenticated-orcid":true,"given":"Martijn F.","family":"Hoes","sequence":"additional","affiliation":[{"name":"Department of Cardiology (M.F.H., M.N., J.J.F.P.L., S.W.), Maastricht University Medical Center, The Netherlands."},{"name":"Department of Clinical Genetics (M.F.H., M.N., J.F.C.G., J.J.F.P.L.), Maastricht University Medical Center, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5691-1634","authenticated-orcid":true,"given":"Miranda","family":"Nabben","sequence":"additional","affiliation":[{"name":"Department of Cardiology (M.F.H., M.N., J.J.F.P.L., S.W.), Maastricht University Medical Center, The Netherlands."},{"name":"Department of Clinical Genetics (M.F.H., M.N., J.F.C.G., J.J.F.P.L.), Maastricht University Medical Center, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6533-9548","authenticated-orcid":true,"given":"Jan F.C.","family":"Glatz","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics (M.F.H., M.N., J.F.C.G., J.J.F.P.L.), Maastricht University Medical Center, The 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