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
Department of Psychiatry, Divisions of Molecular Therapeutics and Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, USA.
New York State Psychiatric Institute, New York, NY, USA.
Nature. 2025 May;641(8063):749-758. doi: 10.1038/s41586-025-08740-6. Epub 2025 Mar 26.
Mitochondrial oxidative phosphorylation (OXPHOS) powers brain activity, and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders. To understand the basis of brain activity and behaviour, there is a need to define the molecular energetic landscape of the brain. 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 modalities 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 .
线粒体氧化磷酸化（OXPHOS）为大脑活动提供能量，线粒体缺陷与神经退行性疾病和神经精神疾病有关。为了理解大脑活动和行为的基础，有必要定义大脑的分子能量格局。在这里，为了弥合认知神经科学和细胞生物学之间的尺度差距，我们开发了一种物理体素化方法，将冷冻的人类冠状半球切片分割成703个与神经成像分辨率相当的体素（3×3×3毫米）。在每个皮质和皮质下脑体素中，我们分析了线粒体表型，包括氧化磷酸化酶活性、线粒体DNA和体积密度，以及线粒体特异性呼吸能力。我们表明，人类大脑包含由拓扑结构和细胞类型驱动的多种线粒体表型。与白质相比，灰质中的线粒体多50%以上。此外，灰质中的线粒体在生物化学上针对能量转化进行了优化，特别是在最近进化的皮质脑区。将这些数据扩展到整个大脑，我们创建了一个反向线性回归模型，该模型整合了多种神经成像模态，以生成全脑线粒体分布和特化图谱。该模型预测了同一供体大脑独立脑区的线粒体特征。这种方法以及由此产生的线粒体表型的线粒体脑图谱为探索支持正常脑功能的分子能量格局提供了基础。该资源还与神经成像数据相关，并定义了与神经精神疾病和神经退行性疾病相关的区域化脑过程的亚细胞基础。所有数据可在http://humanmitobrainmap.bcblab.com获取。
