Organ function declines with age, and large-scale transcriptomic analyses have highlighted differential aging trajectories across tissues. The mechanism underlying shared and organ-selective functional changes across the lifespan, however, still remains poorly understood. Given the central role of mitochondria in powering cellular processes needed to maintain tissue health, we therefore undertook a systematic assessment of respiratory activity across 33 different tissues in young (2.5 months) and old (20 months) mice of both sexes. Our high-resolution mitochondrial respiration atlas reveals: (1) within any group of mice, mitochondrial activity varies widely across tissues, with the highest values consistently seen in heart, brown fat, and kidney; (2) biological sex is a significant but minor contributor to mitochondrial respiration, and its contributions are tissue-specific, with major differences seen in the pancreas, stomach, and white adipose tissue; (3) age is a dominant factor affecting mitochondrial activity, especially across most brain regions, different fat depots, skeletal muscle groups, eyes, and different regions of the gastrointestinal tract; (4) age effects can be sex- and tissue-specific, with some of the largest effects seen in pancreas, heart, adipose tissue, and skeletal muscle; and (5) while aging alters the functional trajectories of mitochondria in a majority of tissues, some are remarkably resilient to age-induced changes. Altogether, our data provide the most comprehensive compendium of mitochondrial respiration and illuminate functional signatures of aging across diverse tissues and organ systems.

Targeted low-throughput studies have previously identified subcellular RNA localization as necessary for cellular functions including polarization, and translocation. Furthermore, these studies link localization to RNA isoform expression, especially 3’ Untranslated Region (UTR) regulation. The recent introduction of genome-wide spatial transcriptomics techniques enables the potential to test if subcellular localization is regulated in situ pervasively. In order to do this, robust statistical measures of subcellular localization and alternative poly-adenylation (APA) at single-cell resolution are needed. Developing a new statistical framework called SPRAWL, we detect extensive cell-type specific subcellular RNA localization regulation in the mouse brain and to a lesser extent mouse liver. We integrated SPRAWL with a new approach to measure cell-type specific regulation of alternative 3’ UTR processing and detected examples of significant correlations between 3’ UTR length and subcellular localization. Included examples, Timp3, Slc32a1, Cxcl14, and Nxph1 have subcellular localization in the mouse brain highly correlated with regulated 3’ UTR processing that includes the use of unannotated, but highly conserved, 3’ ends. Together, SPRAWL provides a statistical framework to integrate multi-omic single-cell resolved measurements of gene-isoform pairs to prioritize an otherwise impossibly large list of candidate functional 3’ UTRs for functional prediction and study. In these studies of data from mice, SPRAWL predicts that 3’ UTR regulation of subcellular localization may be more pervasive than currently known.