A human brain map of mitochondrial respiratory capacity and diversity

• 成果类型: Article
• 署名作者: Mosharov, Eugene V.; Rosenberg, Ayelet M.; Monzel, Anna S.; Osto, Corey A.; Stiles, Linsey; Rosoklija, Gorazd B.; Dwork, Andrew J.; Bindra, Snehal; Junker, Alex; Zhang, Ya; Fujita, Masashi; Mariani, Madeline B.; Bakalian, Mihran; Sulzer, David; De Jager, Philip L.; Menon, Vilas; Shirihai, Orian S.; Mann, J. John; Underwood, Mark D.; Boldrini, Maura; Thiebaut de Schotten, Michel; Picard, Martin
• 署名单位: NewYork-Presbyterian Hospital; Columbia University; New York State Psychiatry Institute; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; Columbia University; NewYork-Presbyterian Hospital; Columbia University; NewYork-Presbyterian Hospital; Columbia University; NewYork-Presbyterian Hospital; Columbia University; NewYork-Presbyterian Hospital; Columbia University; Columbia University; NewYork-Presbyterian Hospital; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); CEA; Universite de Bordeaux; Columbia University; NewYork-Presbyterian Hospital; Columbia University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3007
• DOI: 10.1038/s41586-025-08740-6
• 发表日期: 2025-05-15
• 关键词: cell; cortex; size

摘要

Mitochondrial oxidative phosphorylation (OXPHOS) powers brain activity(1,2), and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders(3,4). To understand the basis of brain activity and behaviour, there is a need to define the molecular energetic landscape of the brain(5-10). Here, to bridge the scale gap between cognitive neuroscience and cell biology, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3 x 3 x 3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes, including OXPHOS enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains diverse mitochondrial phenotypes driven by both topology and cell types. Compared with white matter, grey matter contains >50% more mitochondria. Moreover, the mitochondria in grey matter are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backwards linear regression model that integrates several neuroimaging modalities(11) to generate a brain-wide map of mitochondrial distribution and specialization. This model predicted mitochondrial characteristics in an independent brain region of the same donor brain. This approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain function. This resource also relates to neuroimaging data and defines the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders. All data are available at http://humanmitobrainmap.bcblab.com.