Genetic variation in genes regulating metabolism may be advantageous in some settings but not others. The non-failing adult heart relies heavily on fatty acids as a fuel substrate and source of ATP. In contrast, the failing heart favors glucose as a fuel source. A bootstrap analysis for genes with deviant...
Membrane contact sites (MCSs) facilitate communication and organization of organelles that contribute to fundamental cellular processes. It has become increasingly appreciated how extensive and essential MCSs are for cellular health, and this field is rapidly growing. We use budding yeast as a model system to study the mechanisms of how...
Mitochondria-lysosome contacts are recently identified sites for mediating crosstalk between both organelles, but their role in normal and diseased human neurons remains unknown. We used super-resolution and live-cell microscopy in human iPSC-derived neurons to demonstrate that mitochondria-lysosome contacts can dynamically form in the soma, axons, and dendrites of human neurons,...
Inter-organelle contact sites have become increasingly appreciated as important regulators of cellular homeostasis, and disruption of inter-organelle contact site dynamics and function has been observed in various pathologies. Recently, inter-organelle contact sites between mitochondria and lysosomes were discovered, offering a new mechanism by which these two organelles may directly interact,...
Mitochondrial complex I is the primary entry point for electrons into the mitochondrial electron transport chain that is composed of 45 individual protein subunits that are encoded in both the nuclear and mitochondrial genomes. Mitochondrial complex I sits at an important nexus in the essential bioenergetic, biosynthetic, and signaling functions...
The product of hexokinase (HK) enzymes, glucose-6-phosphate, can be metabolized through glycolysis or directed to alternative pathways, such as the pentose phosphate pathway (PPP) to generate anabolic intermediates. HK1 contains an N-terminal domain that permits mitochondrial binding, but its physiologic significance remains unclear. We generated mice lacking the HK1 mitochondrial-binding...
Mitochondria-derived reactive oxygen species (mROS) are required for the survival, proliferation, and metastasis of cancer cells. The mechanism by which mitochondrial metabolism regulates mROS levels to support cancer cells is not fully understood. To address this, we conducted a metabolism-focused CRISPR/Cas9 genetic screen and uncovered that loss of genes encoding...
Endothelial cells (ECs) require glycolysis for proliferation and migration during angiogenesis; however, the necessity for the mitochondrial respiratory chain during angiogenesis is not known. In this study, we report that inhibition of respiratory chain complex III impairs proliferation, but not migration of ECs in vitro by decreasing the NAD+/NADH ratio....
Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are two devastating neurodegenerative diseases that affect 100,000s of people globally. They have a severe adverse impact on society, yet there are currently no early diagnostic tools or disease-modifying therapies available. Despite their clinical heterogeneity, evidence points to these diseases being on...