The Lab of Organelle Metabolism was established in September 2026 at the National Cerebral and Cardiovascular Center (NCVC) Research Institute. Our laboratory aims to elucidate the molecular mechanisms that govern metabolism within intracellular organelles, particularly mitochondria and lysosomes, and thereby provide a mechanistic basis for understanding the pathophysiology of metabolic diseases, including obesity, diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD).

・What Is Organelle Metabolism?

 Eukaryotic cells contain multiple membrane-bound organelles with specialized functions, such as mitochondria, lysosomes, the endoplasmic reticulum, the Golgi apparatus, and the nucleus. These organelles compartmentalize distinct biochemical reactions and collectively maintain cellular homeostasis.

 Lysosomes serve as the terminal degradative compartment of the cell. Unnecessary cytoplasmic proteins and macromolecules, as well as damaged organelles, are delivered to lysosomes through autophagy, where they are degraded by lysosomal hydrolases. The molecular mechanisms of autophagy were recognized by the 2016 Nobel Prize in Physiology or Medicine awarded to Dr. Yoshinori Ohsumi.

 Mitochondria, in contrast, are central hubs of cellular energy metabolism. They oxidize carbon substrates derived from carbohydrates, amino acids, and fatty acids through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation to generate ATP.

 Cellular metabolism encompasses the biochemical processes by which nutrients and metabolites are degraded, interconverted, and synthesized. These reactions are spatially organized among different intracellular compartments. We define organelle metabolism as the study of how metabolites are generated, consumed, transported, and utilized within and between individual organelles.

Figure 1. Lysosomes mediate the recycling of autophagic cargo

 Autophagy sequesters unnecessary cytoplasmic proteins and damaged organelles within autophagosomes. Autophagosomes subsequently fuse with lysosomes, where their contents are degraded by lysosomal hydrolases. The resulting metabolites are exported from the lysosomal lumen and reutilized for multiple biosynthetic and metabolic processes.

N. Mizushima and M. Komatsu. Cell 2011

・Why Is Organelle Metabolism Important?

 Dysregulation of organelle metabolism during aging or chronic nutritional excess can contribute to the development of metabolic disorders, such as obesity and diabetes. These disorders, in turn, substantially increase the risk of cardiovascular and cerebrovascular diseases.

 Elucidating how organelle metabolism is disrupted and how these alterations contribute to systemic metabolic disease may therefore reveal new therapeutic opportunities for cardiometabolic disorders.

1. Autophagy and Metabolic Disease

 Adipocytes play a central role in the maintenance of systemic metabolic homeostasis. Under conditions of nutrient excess, glucose and lipids that exceed energetic requirements are converted into and stored as triglycerides in adipose tissue. This buffering capacity limits the spillover of excess nutrients into non-adipose tissues, thereby protecting other organs from ectopic lipid accumulation and metabolic overload. Accordingly, understanding the mechanisms that maintain adipocyte function is critical for elucidating the pathogenesis of metabolic disorders.

 Autophagy delivers cytoplasmic constituents to lysosomes for degradation. Our previous studies demonstrated that autophagic activity is physiologically restrained in adipocytes. During aging, this restraint is lost, leading to excessive autophagic degradation of SRC-1 and TIF2, which are required for normal adipocyte function. As a consequence, adipocyte metabolic functions decline, accompanied by fat loss, ectopic fat deposition, and glucose intolerance.

 Conversely, we also demonstrated that adipocyte autophagy contributes to the adaptive response to fasting by facilitating the mobilization of nutrients from adipose tissue to other organs. These findings indicate that the physiological consequences of autophagy are highly dependent on metabolic context.

 Building on these findings, our laboratory is now investigating how metabolites generated through autophagic degradation are exported from lysosomes and subsequently reutilized in cellular metabolism.

Figure 3. Excessive autophagy impairs adipocyte function

 Adipocyte metabolic function is supported by the transcriptional coactivators SRC-1 and TIF2, which enhance PPARγ-dependent transcription and thereby promote lipid synthesis and nutrient uptake. During aging, excessive autophagic activity promotes the degradation of SRC-1 and TIF2, resulting in reduced PPARγ activity and impaired adipocyte function.

T. Yamamuro, et al. Nat. Commun. 2020; T. Yamamuro, et al. Autophagy 2022

2. Mitochondria and Metabolic Disease

 Mitochondria are classically recognized for their ability to oxidize carbon substrates derived from glucose, amino acids, and lipids and convert the resulting energy into ATP. However, our work demonstrated that mitochondria in adipocytes also have a critical anabolic function, supporting the conversion of excess nutrients into storage lipids. We termed this metabolically specialized mitochondrial state “Lipogenic Mitochondria.”

 We found that Lipogenic Mitochondria in adipocytes actively generate phosphoenolpyruvate (PEP). Although mitochondrial PEP had long been implicated in cytosolic glycerolipid synthesis, the mechanism responsible for PEP export across the mitochondrial inner membrane remained unknown.

 We identified SLC25A35 as the mitochondrial PEP exporter. Genetic disruption of Slc25a35 resulted in the accumulation of PEP within mitochondria and impaired lipid synthesis in adipocytes, establishing SLC25A35 as a key component of the mitochondrial PEP shuttle.

 We further demonstrated that this pathway contributes to hepatic steatosis under conditions of nutrient excess. Genetic inhibition of Slc25a35 reduced hepatic lipid accumulation, suggesting that pharmacological inhibition of SLC25A35 may represent a potential therapeutic strategy for fatty liver disease. 

 Organelle metabolism represents a fundamental aspect of cellular physiology across essentially all tissues. Beyond the liver and adipose tissue, organelle-specific metabolic programs contribute to the function of diverse cell types and their adaptation to changing metabolic and physiological demands throughout the body.

 By elucidating the molecular mechanisms that regulate metabolic reactions and metabolite transport within organelles, we aim to uncover fundamental principles of cellular metabolism, deepen our understanding of metabolic and cardiovascular diseases, and ultimately translate these insights into novel therapeutic strategies.

 Organelle Metabolism Laboratory welcomes motivated graduate students, postdoctoral researchers, and research staff interested in pursuing research with us. We seek individuals who share our interests in fundamental cell biology and metabolism and are motivated to address important questions at the interface of basic science and medicine. If you are interested in joining our laboratory, please feel free to contact us at yamamuro.tadashi@ncvc.go.jp.

National Cerebral and Cardiovascular Center

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