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Nat Neurosci. 2019 Oct;22(10):1731-1742. doi: 10.1038/s41593-019-0479-z. Epub 2019 Sep 9.

Cell-type-specific profiling of brain mitochondria reveals functional and molecular diversity.

Fecher C1,2,3, Trovò L1,2, Müller SA2,4, Snaidero N1,2, Wettmarshausen J5,6, Heink S7, Ortiz O8,9,10, Wagner I11, Kühn R8,9,12,13, Hartmann J14, Karl RM14, Konnerth A14,15,16, Korn T7,15, Wurst W2,8,9,15, Merkler D11,17, Lichtenthaler SF2,4,15, Perocchi F5,6,15, Misgeld T18,19,20,21.

Author information

1
Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany.
2
German Center for Neurodegenerative Diseases, Munich, Germany.
3
Graduate School of Systemic Neurosciences, Ludwig-Maximilians University, Munich, Germany.
4
Neuroproteomics, School of Medicine, Klinikum rechts der Isar and Institute for Advanced Study, Technical University of Munich, Munich, Germany.
5
Gene Center Munich, Ludwig-Maximilians University, Munich, Germany.
6
Institute for Diabetes and Obesity, Helmholtz Zentrum München, Munich, Germany.
7
Experimental Neuroimmunology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
8
Institute of Developmental Genetics, Helmholtz Zentrum München, Munich, Germany.
9
Institute of Developmental Genetics, Technical University of Munich, Munich, Germany.
10
Merck KGaA, Darmstadt, Germany.
11
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
12
Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany.
13
Berlin Institute of Health, Berlin, Germany.
14
Institute of Neuroscience, Technical University of Munich, Munich, Germany.
15
Munich Cluster for Systems Neurology, Munich, Germany.
16
Center of Integrated Protein Science, Munich, Germany.
17
Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland.
18
Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany. thomas.misgeld@tum.de.
19
German Center for Neurodegenerative Diseases, Munich, Germany. thomas.misgeld@tum.de.
20
Munich Cluster for Systems Neurology, Munich, Germany. thomas.misgeld@tum.de.
21
Center of Integrated Protein Science, Munich, Germany. thomas.misgeld@tum.de.

Abstract

Mitochondria vary in morphology and function in different tissues; however, little is known about their molecular diversity among cell types. Here we engineered MitoTag mice, which express a Cre recombinase-dependent green fluorescent protein targeted to the outer mitochondrial membrane, and developed an isolation approach to profile tagged mitochondria from defined cell types. We determined the mitochondrial proteome of the three major cerebellar cell types (Purkinje cells, granule cells and astrocytes) and identified hundreds of mitochondrial proteins that are differentially regulated. Thus, we provide markers of cell-type-specific mitochondria for the healthy and diseased mouse and human central nervous systems, including in amyotrophic lateral sclerosis and Alzheimer's disease. Based on proteomic predictions, we demonstrate that astrocytic mitochondria metabolize long-chain fatty acids more efficiently than neuronal mitochondria. We also characterize cell-type differences in mitochondrial calcium buffering via the mitochondrial calcium uniporter (Mcu) and identify regulator of microtubule dynamics protein 3 (Rmdn3) as a determinant of endoplasmic reticulum-mitochondria proximity in Purkinje cells. Our approach enables exploring mitochondrial diversity in many in vivo contexts.

PMID:
31501572
DOI:
10.1038/s41593-019-0479-z

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