TY - JOUR T1 - Heterogeneous Expression of Nuclear Encoded Mitochondrial Genes Distinguishes Inhibitory and Excitatory Neurons JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0232-21.2021 SP - ENEURO.0232-21.2021 AU - Meghan E. Wynne AU - Alicia R. Lane AU - Kaela S. Singleton AU - Stephanie A. Zlatic AU - Avanti Gokhale AU - Erica Werner AU - Duc Duong AU - Jennifer Q. Kwong AU - Amanda J. Crocker AU - Victor Faundez Y1 - 2021/07/26 UR - http://www.eneuro.org/content/early/2021/07/23/ENEURO.0232-21.2021.abstract N2 - Mitochondrial composition varies by organ and their constituent cell types. This mitochondrial diversity likely determines variations in mitochondrial function. However, the heterogeneity of mitochondria in the brain remains underexplored despite the large diversity of cell types in neuronal tissue. Here, we used molecular systems biology tools to address whether mitochondrial composition varies by brain region and neuronal cell type in mice. We reasoned that proteomics and transcriptomics of microdissected brain regions combined with analysis of single cell mRNA sequencing could reveal the extent of mitochondrial compositional diversity. We selected nuclear encoded gene products forming complexes of fixed stoichiometry, such as the respiratory chain complexes and the mitochondrial ribosome, as well as molecules likely to perform their function as monomers, such as the family of SLC25 transporters. We found that the proteome encompassing these nuclear-encoded mitochondrial genes and obtained from microdissected brain tissue segregated the hippocampus, striatum, and cortex from each other. Nuclear-encoded mitochondrial transcripts could only segregate cell types and brain regions when the analysis was performed at the single cell level. In fact, single cell mitochondrial transcriptomes were able to distinguish glutamatergic and distinct types of GABAergic neurons from one another. Within these cell categories, unique SLC25A transporters were able to identify distinct cell subpopulations. Our results demonstrate heterogeneous mitochondrial composition across brain regions and cell types. We postulate that mitochondrial heterogeneity influences regional and cell type specific mechanisms in health and disease.Significance StatementMitochondria are important organelles for maintaining brain health. The composition of proteins making up mitochondria is essential for their function. Disturbances to mitochondria are thought to contribute to neurodegeneration and neurodevelopmental disorders. These conditions typically affect specific brain regions or cell types. Despite the link between mitochondria and diseases with distinct anatomical and cellular patterns, how mitochondrial composition varies across brain regions and cell types remains poorly explored. Here, we analyze mitochondrial composition in different brain regions and cell types in adult mice, showing composition differs by region and cell lineage. Our work provides a resource of genes enriched in certain cell types or regions that improves our understanding of how mitochondrial composition influences brain function in health and disease. ER -