Endoplasmic reticulum stress and mitochondrial dysfunction during aging: Role of sphingolipids |
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| Affiliation: | 1. Department of Medicine (Division of Cardiology), Virginia Commonwealth University, Richmond, VA 23298, United States of America;2. Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, United States of America;3. Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA 23298, United States of America;4. Richmond Department of Veterans Affairs Medical Center, Richmond, VA 23249, United States of America;1. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States of America;2. Department of Chemistry, Vanderbilt University, Nashville, TN 37235, United States of America;3. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, United States of America;1. Institute for Clinical Chemistry, University Hospital and University of Zürich, Zürich, Switzerland;2. Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China;3. Institute for Biochemistry, University of Zürich; Zürich, Switzerland;4. National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, China;1. Pharmaceutics, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino-machi, Nobeoka, Miyazaki 882-8508, Japan;2. Faculty of Pharmacy, Yasuda Women''s University, Hiroshima, Japan;3. Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan;4. Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan;1. Nanoscopy, Istituto Italiano Tecnologia, Via Enrico Melen 83, 16152, Genova, Italy;2. Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132, Genova, Italy;3. Department of Physics (DIFILAB), University of Genoa, Via Dodecaneso 33, 16146, Genoa, Italy;4. DIMES, Department of Experimental Medicine, University of Genoa, Genoa, Italy;5. IRCCS Ospedale Policlinico San Martino, Genoa, Italy;6. Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari, Medical School, Piazza Giulio Cesare 11, 70124, Bari, Italy |
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| Abstract: | The endoplasmic reticulum (ER) plays a key role in the regulation of protein folding, lipid synthesis, calcium homeostasis, and serves as a primary site of sphingolipid biosynthesis. ER stress (ER dysfunction) participates in the development of mitochondrial dysfunction during aging. Mitochondria are in close contact with the ER through shared mitochondria associated membranes (MAM). Alteration of sphingolipids contributes to mitochondria-driven cell injury. Cardiolipin is a phospholipid that is critical to maintain enzyme activity in the electron transport chain. The aim of the current study was to characterize the changes in sphingolipids and cardiolipin in ER, MAM, and mitochondria during the progression of aging in young (3 mo.), middle (18 mo.), and aged (24 mo.) C57Bl/6 mouse hearts. ER stress increased in hearts from 18 mo. mice and mice exhibited mitochondrial dysfunction by 24 mo. Hearts were pooled to isolate ER, MAM, and subsarcolemmal mitochondria (SSM). LC-MS/MS quantification of lipid content showed that aging increased ceramide content in ER and MAM. In addition, the contents of sphingomyelin and monohexosylceramides are also increased in the ER from aged mice. Aging increased the total cardiolipin content in the ER. Aging did not alter the total cardiolipin content in mitochondria or MAM yet altered the composition of cardiolipin with aging in line with increased oxidative stress compared to young mice. These results indicate that alteration of sphingolipids can contribute to the ER stress and mitochondrial dysfunction that occurs during aging. |
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