Recruitment and remodeling of peridroplet mitochondria in human adipose tissue
Rebeca Acín-Perez,
Anton Petcherski,
Michaela Veliova,
Ilan Y. Benador,
Essam A. Assali,
Georgia Colleluori,
Saverio Cinti,
Alexandra J. Brownstein,
Siyouneh Baghdasarian,
Masha J. Livhits,
Michael W. Yeh,
Karthickeyan Chella Krishnan,
Laurent Vergnes,
Nathan C. Winn,
Jaume Padilla,
Marc Liesa,
Harold S. Sacks,
Orian S. Shirihai
Affiliations
Rebeca Acín-Perez
Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA; Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA
Anton Petcherski
Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA; Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA
Michaela Veliova
Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, 90095, USA
Ilan Y. Benador
Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA; Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA; Nutrition and Metabolism, Graduate Medical Sciences, Boston University School of Medicine, Boston, MA, 02118, USA
Essam A. Assali
Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA; Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA; Department of Clinical Biochemistry, School of Medicine, Ben Gurion University of The Negev, Beer-Sheva, Israel
Georgia Colleluori
Department of Experimental and Clinical Medicine, Center of Obesity, Marche Polytechnic University, Ancona, 60020, Italy
Saverio Cinti
Department of Experimental and Clinical Medicine, Center of Obesity, Marche Polytechnic University, Ancona, 60020, Italy
Alexandra J. Brownstein
Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA; Molecular Cellular Integrative Physiology, University of California, Los Angeles, CA, 90095, USA
Siyouneh Baghdasarian
Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA; Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA
Masha J. Livhits
Section of Endocrine Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA
Michael W. Yeh
Section of Endocrine Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA
Karthickeyan Chella Krishnan
Department of Medicine, Division of Cardiology, University of California, Los Angeles, Los Angeles, CA, USA; Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, OH, USA
Laurent Vergnes
Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA
Nathan C. Winn
Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA; Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
Jaume Padilla
Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA; Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA
Marc Liesa
Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA; Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, 90095, USA; Molecular Cellular Integrative Physiology, University of California, Los Angeles, CA, 90095, USA; Corresponding author. Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
Harold S. Sacks
Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA; Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA; Endocrine and Diabetes Division, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA; Corresponding author. Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
Orian S. Shirihai
Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA; Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, 90095, USA; Nutrition and Metabolism, Graduate Medical Sciences, Boston University School of Medicine, Boston, MA, 02118, USA; Molecular Cellular Integrative Physiology, University of California, Los Angeles, CA, 90095, USA; Corresponding author. Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
Beige adipocyte mitochondria contribute to thermogenesis by uncoupling and by ATP-consuming futile cycles. Since uncoupling may inhibit ATP synthesis, it is expected that expenditure through ATP synthesis is segregated to a disparate population of mitochondria. Recent studies in mouse brown adipocytes identified peridroplet mitochondria (PDM) as having greater ATP synthesis and pyruvate oxidation capacities, while cytoplasmic mitochondria have increased fatty acid oxidation and uncoupling capacities. However, the occurrence of PDM in humans and the processes that result in their expansion have not been elucidated. Here, we describe a novel high-throughput assay to quantify PDM that is successfully applied to white adipose tissue from mice and humans. Using this approach, we found that PDM content varies between white and brown fat in both species. We used adipose tissue from pheochromocytoma (Pheo) patients as a model of white adipose tissue browning, which is characterized by an increase in the capacity for energy expenditure. In contrast with control subjects, PDM content was robustly increased in the periadrenal fat of Pheo patients. Remarkably, bioenergetic changes associated with browning were primarily localized to PDM compared to cytoplasmic mitochondria (CM). PDM isolated from periadrenal fat of Pheo patients had increased ATP-linked respiration, Complex IV content and activity, and maximal respiratory capacity. We found similar changes in a mouse model of re-browning where PDM content in whitened brown adipose tissue was increased upon re-browning induced by decreased housing temperature. Taken together, this study demonstrates the existence of PDM as a separate functional entity in humans and that browning in both mice and humans is associated with a robust expansion of peri-droplet mitochondria characterized by increased ATP synthesis linked respiration.
