The Haigis laboratory aims to elucidate how basic regulatory mechanisms of mitochondrial metabolism impact human health, aging and age-related diseases, such as diabetes. We utilize a cross-disciplinary platform that integrates biochemical, cell biological, and organismal approaches to study mitochondrial metabolism with a goal to identify new mechanisms that regulate mitochondrial metabolism and apply this knowledge of regulation to deepen our understanding of fundamental cell biology and relevance to diseases. To achieve these goals, the Haigis lab has employed an orthogonal approach of multi-omics technology combined with an in-house platform of metabolomics, signaling, mitochondrial biochemistry (in lab Seahorse respirometer and 3 mass spectrometers for metabolomic studies), and cell biology to identify novel metabolic nodes relevant to cellular metabolism. This approach is exemplified in ongoing projects

1. Aging, obesity and immunity. The Haigis lab has discovered new molecular mechanisms that contribute to our understanding of the role of metabolism in T cells and the importance of these pathways in during physiological states, such as aging and obesity. We have discovered that one carbon metabolism was blunted during the activation of aged T cells, and that addition of one carbon intermediates could enhance T cell activation (PMC6310842). Most recently, we investigated the effects of systemic stresses, such as obesity on immunity. Our studies identifying metabolic liabilities that metabolic rewiring of fatty acids to impact immunity during obesity was recently published in Cell in 2020 (PMCID in progress).

2. Post-translational regulation of metabolism in mitochondria. We have identified new molecular mechanisms that contribute to our understanding of how fuels are oxidized in the mitochondria by sirtuins and prolyl hydroxylases. For example, we mapped the mitochondrial sirtuin interactome and determined that SIRT3 mediates membrane potential homeostasis during stress (PMC5134900). Next, we discovered that the proline hydroxylase, PHD3, hydroxylates acetyl coA carboxylase 2 to regulate lipid metabolism in skeletal muscle (PMCID in progress). This work led us to establish novel assays of lipid metabolism and place PHD3 in a new signaling pathway relevant to metabolic homeostasis and physiology.