{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T03:57:31Z","timestamp":1790913451649,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,28]]},"group-title":"Cell Biology","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Barth syndrome (BTHS) is an X-linked mitochondrial disorder caused by loss-of-function mutations in\n                    <jats:italic>TAFAZZIN<\/jats:italic>\n                    (\n                    <jats:italic>TAZ<\/jats:italic>\n                    ), resulting in defective cardiolipin (CL) remodeling, cardiomyopathy, and premature death. The mechanisms linking\n                    <jats:italic>TAZ<\/jats:italic>\n                    deficiency to impaired mitochondrial quality control remain incompletely understood, and there are no disease-modifying therapies available for BTHS. Here, we investigated the role of Acyl-CoA Lysocardiolipin Acyltransferase-1 (ALCAT1), a stress-inducible phospholipid-remodeling enzyme, in BTHS cardiomyopathy.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Inducible\n                    <jats:italic>TAZ<\/jats:italic>\n                    knockdown (\n                    <jats:italic>\n                      TAZ\n                      <jats:sub>KD<\/jats:sub>\n                    <\/jats:italic>\n                    ) and cardiomyocyte-specific\n                    <jats:italic>TAZ<\/jats:italic>\n                    knockout (\n                    <jats:italic>\n                      TAZ\n                      <jats:sup>cKO<\/jats:sup>\n                    <\/jats:italic>\n                    ) mice were used to determine the effects of genetic\n                    <jats:italic>ALCAT1<\/jats:italic>\n                    deletion or pharmacological inhibition with Juvenatin, a highly selective small molecule ALCAT1 inhibitor. Cardiac function, exercise capacity, mitochondrial function, lipid remodeling, lysosomal function, and mitophagic flux were assessed.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    ALCAT1 was markedly upregulated in\n                    <jats:italic>TAZ<\/jats:italic>\n                    -deficient hearts. Genetic\n                    <jats:italic>ALCAT1<\/jats:italic>\n                    deletion attenuated cardiac dysfunction in\n                    <jats:italic>\n                      TAZ\n                      <jats:sub>KD<\/jats:sub>\n                    <\/jats:italic>\n                    mice. Juvenatin similarly improved cardiac function in\n                    <jats:italic>\n                      TAZ\n                      <jats:sub>KD<\/jats:sub>\n                    <\/jats:italic>\n                    mice and reversed established cardiomyopathy in\n                    <jats:italic>\n                      TAZ\n                      <jats:sup>cKO<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Genetic or pharmacological ALCAT1 inhibition improved mitochondrial ultrastructure and respiration and reduced mitochondrial oxidative stress. These benefits occurred without correcting the characteristic CL abnormalities caused by\n                    <jats:italic>TAZ<\/jats:italic>\n                    deficiency. Instead, ALCAT1 deletion or inhibition corrected pathological phosphatidylinositol remodeling, normalized phosphoinositide signaling, and restored lysosomal function and mitophagic flux, leading to improved mitochondrial quality control in\n                    <jats:italic>TAZ<\/jats:italic>\n                    -deficient cells.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>ALCAT1 contributes to BTHS cardiomyopathy through a CL-independent pathway involving dysregulated phosphatidylinositol\/phosphoinositide signaling, lysosomal dysfunction, and impaired mitophagy. Genetic and pharmacological targeting of ALCAT1 restores mitochondrial and cardiac function despite persistent CL abnormalities, establishing ALCAT1 as a promising disease-modifying therapeutic target for BTHS.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.24.754267","type":"posted-content","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:05:22Z","timestamp":1790611522000},"source":"Crossref","is-referenced-by-count":0,"title":["Targeting ALCAT1 Ameliorates Cardiomyopathy in Barth Syndrome"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8489-3699","authenticated-orcid":false,"given":"Jun","family":"Zhang","sequence":"first","affiliation":[{"name":"Sam and Ann Barshop Institute for Longevity and Aging Studies, Department of Pharmacology, UT Health San Antonio, San Antonio, TX 78229, USA"},{"name":"Department of Medicine, Physiology and Biophysics, University of California, Irvine, School of Medicine, Irvine, CA 92697, 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