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Nature neuroscience
10, 2019;22 (10): 1731-1742.

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

Caroline Fecher, Laura Trovò, Stephan A Müller, Nicolas Snaidero, Jennifer Wettmarshausen, Sylvia Heink, Oskar Ortiz, Ingrid Wagner, Ralf Kühn, Jana Hartmann, Rosa Maria Karl, Arthur Konnerth, Thomas Korn, Wolfgang Wurst, Doron Merkler, Stefan F Lichtenthaler, Fabiana Perocchi, Thomas Misgeld
Author Information
  1. Caroline Fecher: Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany. ORCID
  2. Laura Trovò: Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany.
  3. Stephan A Müller: German Center for Neurodegenerative Diseases, Munich, Germany. ORCID
  4. Nicolas Snaidero: Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany.
  5. Jennifer Wettmarshausen: Gene Center Munich, Ludwig-Maximilians University, Munich, Germany.
  6. Sylvia Heink: Experimental Neuroimmunology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. ORCID
  7. Oskar Ortiz: Institute of Developmental Genetics, Helmholtz Zentrum München, Munich, Germany.
  8. Ingrid Wagner: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
  9. Ralf Kühn: Institute of Developmental Genetics, Helmholtz Zentrum München, Munich, Germany. ORCID
  10. Jana Hartmann: Institute of Neuroscience, Technical University of Munich, Munich, Germany.
  11. Rosa Maria Karl: Institute of Neuroscience, Technical University of Munich, Munich, Germany.
  12. Arthur Konnerth: Institute of Neuroscience, Technical University of Munich, Munich, Germany.
  13. Thomas Korn: Experimental Neuroimmunology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. ORCID
  14. Wolfgang Wurst: German Center for Neurodegenerative Diseases, Munich, Germany.
  15. Doron Merkler: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland. ORCID
  16. Stefan F Lichtenthaler: German Center for Neurodegenerative Diseases, Munich, Germany.
  17. Fabiana Perocchi: Gene Center Munich, Ludwig-Maximilians University, Munich, Germany.
  18. Thomas Misgeld: Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany. thomas.misgeld@tum.de. ORCID
PMID: 31501572 DOI: 10.1038/s41593-019-0479-z

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.

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MeSH Term

Alzheimer Disease
Amyotrophic Lateral Sclerosis
Animals
Astrocytes
Brain
Calcium Signaling
Cells, Cultured
Cerebellum
Fatty Acids
Humans
Mice
Mice, Transgenic
Mitochondria
Mitochondrial Membranes
Neurons
Proteomics
Purkinje Cells

Chemicals

Fatty Acids
Journal Article Research Support, Non-U.S. Gov't

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