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The small intestine, as the primary site of nutrient absorption, integrates signals from dietary components and gut microbiota to coordinate systemic energy balance, metabolism, and glucose homeostasis alongside other tissues such as the pancreas, liver, and brain. Nuclear receptors represent one mechanism by which the intestinal epithelium senses and respond to dietary signals via transcriptional regulation of metabolic programs. The Peroxisome Proliferator Activated Receptors (PPARs), including PPARα, PPARδ, and PPARγ, are lipid-responsive nuclear hormone receptors. PPAR transcriptional activity is highly context-dependent, shaped by the availability and affinity of their lipid ligands and co-regulators as well as by cell and tissue types. Whereas PPARγ and PPARδ are established regulators of glucose homeostasis, acting in white adipose tissue, skeletal muscle, and liver to improve insulin sensitivity, PPARα has been primarily associated with hepatic lipid metabolism, where it promotes fatty acid transport, β-oxidation, and ketogenesis. Due to their roles in lipid metabolism and anti-inflammatory processes, selective PPAR agonists are being actively pursued as therapies in clinical and pre-clinical studies for metabolic diseases. Thus, it is critical to improve our understanding of the context-specific and tissue-specific effects of PPAR signaling.

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Current Issue

An atlas of mitochondrial ATP synthase activity across the lifespan

Muzna Saqib, Dylan C. Sarver, Christy M. Nguyen, Fangluo Chen, ... G. William Wong

An atlas of mitochondrial ATP synthase activity across the lifespan

Mitochondrial dysfunction and declining energy production are hallmarks of aging, yet we lack a comprehensive systems-level view of ATP synthase (Complex V) activity across tissues, sex, and age. To overcome this, we leveraged a recently developed method to directly quantify complex V hydrolytic activity at scale in 32 tissues from young (10 weeks) and old (80 weeks) male and female mice. Our high-resolution atlas reveals several notable findings: 1) complex V activity differs markedly across tissues, with the highest levels seen in contractile organs such as the heart and striated muscles (quadriceps, hamstring, diaphragm, tongue); 2) sex influences complex V activity in a tissue-specific manner, with significant differences seen in the heart, liver, fat depots, pancreas, spleen, tongue, and cortex; 3) aging has a much larger impact than sex on complex V activity, with a greater number of age-dependent changes seen across tissues; 4) the directionality and magnitude of change in complex V activity across sex and age is variable and tissue dependent; 5) the expression of complex V related genes in human and mouse tissues across age shows only partial concordance with complex V activity, suggesting functional modulation by posttranscriptional mechanisms. This compendium of ATP synthase activity highlights organ-level variations in the mode and tempo of aging, affording an unprecedented view of the shared and divergent changes in ATP synthase function across sex and organ systems. Our data provide a valuable reference for comparative studies of mitochondrial adaptations across space and time, and in pathophysiological contexts.

Articles in Press

An atlas of mitochondrial ATP synthase activity across the lifespan

Muzna Saqib, Dylan C. Sarver, Christy M. Nguyen, Fangluo Chen, ... G. William Wong

An atlas of mitochondrial ATP synthase activity across the lifespan

Mitochondrial dysfunction and declining energy production are hallmarks of aging, yet we lack a comprehensive systems-level view of ATP synthase (Complex V) activity across tissues, sex, and age. To overcome this, we leveraged a recently developed method to directly quantify complex V hydrolytic activity at scale in 32 tissues from young (10 weeks) and old (80 weeks) male and female mice. Our high-resolution atlas reveals several notable findings: 1) complex V activity differs markedly across tissues, with the highest levels seen in contractile organs such as the heart and striated muscles (quadriceps, hamstring, diaphragm, tongue); 2) sex influences complex V activity in a tissue-specific manner, with significant differences seen in the heart, liver, fat depots, pancreas, spleen, tongue, and cortex; 3) aging has a much larger impact than sex on complex V activity, with a greater number of age-dependent changes seen across tissues; 4) the directionality and magnitude of change in complex V activity across sex and age is variable and tissue dependent; 5) the expression of complex V related genes in human and mouse tissues across age shows only partial concordance with complex V activity, suggesting functional modulation by posttranscriptional mechanisms. This compendium of ATP synthase activity highlights organ-level variations in the mode and tempo of aging, affording an unprecedented view of the shared and divergent changes in ATP synthase function across sex and organ systems. Our data provide a valuable reference for comparative studies of mitochondrial adaptations across space and time, and in pathophysiological contexts.

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