A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity

Mitochondria are a diverse family of organelles that specialize to accomplish complimentary functions ^1-3. All mitochondria share general features, but not all mitochondria are created equal⁴.Here we develop a quantitative pipeline to define the degree of molecular specialization among different mitochondrial phenotypes - or mitotypes. By distilling hundreds of validated mitochondrial genes/proteins into 149 biologically interpretable MitoPathway scores (MitoCarta 3.0 ⁵) the simple mitotyping pipeline allows investigators to quantify and interpret mitochondrial diversity and plasticity from transcriptomics data across a variety of natural and experimental contexts. We show that mouse and human multi-organ mitotypes segregate along two main axes of mitochondrial specialization, contrasting anabolic (liver) and catabolic (brain) tissues. In the brain, we show cell-type-specific enrichment of MitoPathway at the single cell level. In cultured primary human fibroblasts exhibiting robust time-dependent and treatment-induced metabolic plasticity ^6-8, we demonstrate how the mitotype of a given cell type recalibrates i) over time in parallel with hallmarks of aging, and ii) in response to genetic, pharmacological, and metabolic perturbations. Investigators can now use MitotypeExplorer.org and the associated code to visualize, quantify and interpret the multivariate space of mitochondrial biology.