A human brain map of mitochondrial respiratory capacity and diversity

Eugene V. Mosharov, Ayelet M. Rosenberg, Anna S. Monzel, Corey A. Osto, Linsey Stiles, Gorazd B. Rosoklija, Andrew J. Dwork, Snehal Bindra, Alex Junker, Ya Zhang, Masashi Fujita, Madeline B. Mariani, Mihran Bakalian, David Sulzer, Philip L. Jager, Vilas Menon, Orian S. Shirihai, J. John Mann, Mark D. Underwood, Maura Boldrini, Michel Thiebaut de Schotten () and Martin Picard ()
Additional contact information
Eugene V. Mosharov: Columbia University Irving Medical Center
Ayelet M. Rosenberg: Columbia University Irving Medical Center
Anna S. Monzel: Columbia University Irving Medical Center
Corey A. Osto: University of California Los Angeles
Linsey Stiles: University of California Los Angeles
Gorazd B. Rosoklija: New York State Psychiatric Institute
Andrew J. Dwork: New York State Psychiatric Institute
Snehal Bindra: Columbia University Irving Medical Center
Alex Junker: Columbia University Irving Medical Center
Ya Zhang: Columbia University Irving Medical Center
Masashi Fujita: Columbia University Irving Medical Center
Madeline B. Mariani: New York State Psychiatric Institute
Mihran Bakalian: New York State Psychiatric Institute
David Sulzer: Columbia University Irving Medical Center
Philip L. Jager: Columbia University Irving Medical Center
Vilas Menon: Columbia University Irving Medical Center
Orian S. Shirihai: University of California Los Angeles
J. John Mann: New York State Psychiatric Institute
Mark D. Underwood: New York State Psychiatric Institute
Maura Boldrini: New York State Psychiatric Institute
Michel Thiebaut de Schotten: Brain Connectivity and Behaviour Laboratory
Martin Picard: Columbia University Irving Medical Center

Nature, 2025, vol. 641, issue 8063, 749-758

Abstract: Abstract Mitochondrial oxidative phosphorylation (OXPHOS) powers brain activity1,2, and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders3,4. To understand the basis of brain activity and behaviour, there is a need to define the molecular energetic landscape of the brain5–10. 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 × 3 × 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 modalities11 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 .

Date: 2025
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DOI: 10.1038/s41586-025-08740-6

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