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This effect is in part caused by a decline in mitochondrial function as well as by a reduction in lysosomal acidification. Because both mitochondria and lysosomes can alter one another's function, it remains unclear which initiating dysfunction sets off the detrimental cascade of LT, ultimately leading to \u03b2\u2010cell failure. Here, we investigated the effects of restoring lysosomal acidity on mitochondrial function under LT. Our results show that LT induces a dose\u2010dependent lysosomal alkalization accompanied by an increase in mitochondrial mass. This increase is due to a reduction in mitochondrial turnover as analyzed by MitoTimer, a fluorescent protein for which the emission is regulated by mitochondrial clearance rate. Mitochondrial oxygen consumption rate, citrate synthase activity, and ATP content are all reduced by LT. Restoration of lysosomal acidity using lysosome\u2010targeted nanoparticles is accompanied by stimulation of mitochondrial turnover as revealed by mitophagy measurements and the recovery of mitochondrial mass. Remarkably, re\u2010acidification restores citrate synthase activity and ATP content in an insulin secreting \u03b2\u2010cell line (INS\u20101). Furthermore, nanoparticle\u2010mediated lysosomal reacidification rescues mitochondrial maximal respiratory capacity in both INS\u20101 cells and primary mouse islets. Therefore, our results indicate that mitochondrial dysfunction is downstream of lysosomal alkalization under lipotoxic conditions and that recovery of lysosomal acidity is sufficient to restore the bioenergetic defects.\u2014Assali, E. A., Shlomo, D., Zeng, J., Taddeo, E. P., Trudeau, K. M., Erion, K. A., Colby, A. H., Grinstaff, M. W., Liesa, M., Las, G., Shirihai, O. S. Nanoparticle\u2010mediated lysosomal reacidification restores mitochondrial turnover and function in \u03b2 cells under lipotoxicity. 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California USA"}]},{"given":"Dovi","family":"Shlomo","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry Faculty of Health Sciences Ben Gurion University  Beer-Sheva Israel"}]},{"given":"Jialiu","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Boston University  Boston Massachusetts USA"},{"name":"Department of Chemistry Boston University  Boston Massachusetts USA"},{"name":"Department of Medicine Boston University  Boston Massachusetts USA"}]},{"given":"Evan P.","family":"Taddeo","sequence":"additional","affiliation":[{"name":"Division of Endocrinology Department of Medicine University of California  Los Angeles Los Angeles California USA"}]},{"given":"Kyle M.","family":"Trudeau","sequence":"additional","affiliation":[{"name":"Obesity and Nutrition Section Department of Medicine Evans Biomedical Research Center Boston University School of Medicine  Boston Massachusetts USA"}]},{"given":"Karel 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Los Angeles Los Angeles California USA"},{"name":"Molecular Biology Institute University of California  Los Angeles Los Angeles California USA"}]},{"given":"Guy","family":"Las","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry Faculty of Health Sciences Ben Gurion University  Beer-Sheva Israel"}]},{"given":"Orian S.","family":"Shirihai","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry Faculty of Health Sciences Ben Gurion University  Beer-Sheva Israel"},{"name":"Division of Endocrinology Department of Medicine University of California  Los Angeles Los Angeles California 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