Distinguished Scientist Seminar Series featuring Gökhan S. Hotamışlıgil, MD, PhD – “Regulation of mitochondrial structure and function during metabolic cycles and stress.”
Distinguished Scientist Seminar Series
Gökhan S. Hotamışlıgil, MD, PhD
James S. Simmons Professor of Genetics & Metabolism
Director, Sabri Ülker Center for Nutrient, Genetics & Metabolic Research
Director, Harvard Chan Research Center on Causes and Prevention of Cardiovascular Disease
Harvard-MIT Broad Institute
Location: New Research Building Auditorium and via Zoom (https://georgetown.zoom.us/j/95197826709)
Title & Abstract:
“Regulation of mitochondrial structure and function during metabolic cycles and stress.”
Organs and tissues exhibit distinct features of structural organization at various scales to meet functional demands and adapt to challenges to maintain homeostasis and viability. However, detailed resolution of intracellular molecular architecture in native tissue environment has not yet been determined and how molecular architectural form and its regulation relates to metabolic function remains to be understood in vivo. In our earlier work, we have observed that in obesity, interactions between the mitochondria and endoplasmic reticulum are significantly enriched, resulting in mitochondrial dysfunction and excess production of reactive oxygen species in the liver. Recently, we explored the subcellular architectural organization in native tissue environment under physiological metabolic fluctuations and during obesity in extreme detail and explore its regulatory impact on metabolic homeostasis.
We completed resolution of the 3-dimensional organelle structural organization in large (at least 2.8×105μm3) volumes of intact liver tissue derived from lean and obese mice and during feeding and fasting states at high resolution (8nm isotropic pixel size) using enhanced focused ion beam scanning electron microscopy (FIB-SEM), followed by deep-learning-based image segmentation, combined with biochemical and physiological approaches, and 3-D constructions. We demonstrated that hepatic subcellular architecture undergoes massive structural re-organization in obesity characterized by marked disorganization of stacks of ER sheets and predominance of ER tubules, as well as its interactions with mitochondria. Recently, we also resolved hepatic subcellular spatial organization in response to nutritional challenges and as a function of liver zonation. We identified that fasting leads to remodeling of the ER architecture in hepatocytes, characterized by the induction of single rough ER sheet around the mitochondria and marked changes in mitochondrial morphology. These alterations are enriched in periportal and mid-lobular but not in pericentral hepatocytes. Ribosome receptor binding protein1, RRBP1, is required to enable fasting-induced ER sheet-mitochondria interactions and to regulate hepatic fatty acid oxidation. In obesity, ER-mitochondria interactions are distinct and fail to exhibit dynamic adaptive regulation capacity. Finally, we discovered a novel mechanism for the generation of excess hepatic reactive oxygen species in obesity which relates to multicompartmental CoQ synthesis and its impact on mitochondrial electron transport chain.
These findings demonstrate that hepatic subcellular molecular architecture is highly dynamic and regulated, integrated with the metabolic program of the cell, and critical for adaptive homeostasis and metabolic flexibility of the organism.