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

Research output: Contribution to journalArticlepeer-review

154 Scopus citations

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.

Original languageEnglish
Pages (from-to)1731-1742
Number of pages12
JournalNature Neuroscience
Volume22
Issue number10
DOIs
StatePublished - 1 Oct 2019

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