Non-cell autonomous regulation of cell-cell signaling and differentiation by mitochondrial ROS.

Mitochondrial reactive oxygen species (ROS) function intrinsically within cells to induce cell damage, regulate transcription, and cause genome instability. However, we know little about how mitochondrial ROS production non-cell autonomously impacts cell-cell signaling. Here, we show that mitochondrial dysfunction inhibits the plasma membrane localization of cell surface receptors that drive cell-cell communication during oogenesis.

Proteolytic activation of fatty acid synthase signals pan-stress resolution.

Chronic stress and inflammation are both outcomes and major drivers of many human diseases. Sustained responsiveness despite mitigation suggests a failure to sense resolution of the stressor. Here we show that a proteolytic cleavage event of fatty acid synthase (FASN) activates a global cue for stress resolution in Caenorhabditis elegans.

Finishing the egg.

Gamete development is a fundamental process that is highly conserved from early eukaryotes to mammals. As germ cells develop, they must coordinate a dynamic series of cellular processes that support growth, cell specification, patterning, the loading of maternal factors (RNAs, proteins, and nutrients), differentiation of structures to enable fertilization and ensure embryonic survival, and other processes that make a functional oocyte. To achieve these goals, germ cells integrate a complex milieu of environmental and developmental signals to produce fertilizable eggs.

Beyond energy and growth: the role of metabolism in developmental signaling, cell behavior and diapause.

Metabolism is crucial for development through supporting cell growth, energy production, establishing cell identity, developmental signaling and pattern formation. In many model systems, development occurs alongside metabolic transitions as cells differentiate and specialize in metabolism that supports new functions. Some cells exhibit metabolic flexibility to circumvent mutations or aberrant signaling, whereas other cell types require specific nutrients for developmental progress.

The role of metabolism in cellular quiescence.

Cellular quiescence is a dormant, non-dividing cell state characterized by significant shifts in physiology and metabolism. Quiescence plays essential roles in a wide variety of biological processes, ranging from microbial sporulation to human reproduction and wound repair. Moreover, when the regulation of quiescence is disrupted, it can drive cancer growth and compromise tissue regeneration after injury.

Highly conserved shifts in ubiquitin-proteasome system (UPS) activity drive mitochondrial remodeling during quiescence.

Defects in cellular proteostasis and mitochondrial function drive many aspects of infertility, cancer, and other age-related diseases. All of these conditions rely on quiescent cells, such as oocytes and adult stem cells, that reduce their activity and remain dormant as part of their roles in tissue homeostasis, reproduction, and even cancer recurrence. Using a multi-organism approach, we show that dynamic shifts in the ubiquitin proteasome system drive mitochondrial remodeling during cellular quiescence.

Mitochondrial respiratory quiescence: A new model for examining the role of mitochondrial metabolism in development.

Mitochondria are vital organelles with a central role in all aspects of cellular metabolism. As a means to support the ever-changing demands of the cell, mitochondria produce energy, drive biosynthetic processes, maintain redox homeostasis, and function as a hub for cell signaling. While mitochondria have been widely studied for their role in disease and metabolic dysfunction, this organelle has a continually evolving role in the regulation of development, wound repair, and regeneration.

Heritable shifts in redox metabolites during mitochondrial quiescence reprogramme progeny metabolism.

Changes in maternal diet and metabolic defects in mothers can profoundly affect health and disease in their progeny. However, the biochemical mechanisms that induce the initial reprogramming events at the cellular level have remained largely unknown owing to limitations in obtaining pure populations of quiescent oocytes. Here, we show that the precocious onset of mitochondrial respiratory quiescence causes a reprogramming of progeny metabolic state.

Dietary Lipids Modulate Notch Signaling and Influence Adult Intestinal Development and Metabolism in Drosophila.

Tissue homeostasis involves a complex balance of developmental signals and environmental cues that dictate stem cell function. We found that dietary lipids control enteroendocrine cell production from Drosophila posterior midgut stem cells. Dietary cholesterol influences new intestinal cell differentiation in an Hr96-dependent manner by altering the level and duration of Notch signaling.

The role of metabolic states in development and disease.

During development, cells adopt distinct metabolic strategies to support growth, produce energy, and meet the demands of a mature tissue. Some of these metabolic states maintain a constrained program of nutrient utilization, while others providing metabolic flexibility as a means to couple developmental progression with nutrient availability. Here we discuss our understanding of metabolic programs, and how they support specific aspects of animal development.

Electron Transport Chain Remodeling by GSK3 during Oogenesis Connects Nutrient State to Reproduction.

Reproduction is heavily influenced by nutrition and metabolic state. Many common reproductive disorders in humans are associated with diabetes and metabolic syndrome. We characterized the metabolic mechanisms that support oogenesis and found that mitochondria in mature Drosophila oocytes enter a low-activity state of respiratory quiescence by remodeling the electron transport chain (ETC).

Steroid Signaling Establishes a Female Metabolic State and Regulates SREBP to Control Oocyte Lipid Accumulation.

Disruptions in energy homeostasis severely affect reproduction in many organisms and are linked to several reproductive disorders in humans. As a result, understanding the mechanisms that control nutrient accumulation in the oocyte will provide valuable insights into the links between metabolic disease and reproductive dysfunction. We show that the steroid hormone ecdysone functions in Drosophila to control lipid metabolism and support oocyte production.

Coordination of triacylglycerol and cholesterol homeostasis by DHR96 and the Drosophila LipA homolog magro.

Although transintestinal cholesterol efflux has been identified as an important means of clearing excess sterols, the mechanisms that underlie this process remain poorly understood. Here, we show that magro, a direct target of the Drosophila DHR96 nuclear receptor, is required in the intestine to maintain cholesterol homeostasis. magro encodes a LipA homolog that is secreted from the anterior gut into the intestinal lumen to digest dietary triacylglycerol.

The DHR96 nuclear receptor controls triacylglycerol homeostasis in Drosophila.

Triacylglycerol (TAG) homeostasis is an integral part of normal physiology and essential for proper energy metabolism. Here we show that the single Drosophila ortholog of the PXR and CAR nuclear receptors, DHR96, plays an essential role in TAG homeostasis. DHR96 mutants are sensitive to starvation, have reduced levels of TAG in the fat body and midgut, and are resistant to diet-induced obesity, while DHR96 overexpression leads to starvation resistance and increased TAG levels.