Exploring the Pivotal Role of Signaling and Mitochondria
in Aging, Cancer, and Immunity
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Innate immune responses
Nature (2025)
Mitochondrial stress pathways protect mitochondrial health from cellular insults. However, their role under physiological conditions is largely unknown. Here, using 18 single, double and triple whole-body and tissue-specific knockout and mutant mice, along with systematic mitochondrial morphology analysis, untargeted metabolomics and RNA sequencing, we discovered that the synergy between two stress-responsive systems—the ubiquitin E3 ligase Parkin and the metalloprotease OMA1—safeguards mitochondrial structure and genome by mitochondrial fusion, mediated by the outer membrane GTPase MFN1 and the inner membrane GTPase OPA1. Whereas the individual loss of Parkin or OMA1 does not affect mitochondrial integrity, their combined loss results in small body size, low locomotor activity, premature death, mitochondrial abnormalities and innate immune responses. Thus, our data show that Parkin and OMA1 maintain a dual regulatory mechanism that controls mitochondrial fusion at the two membranes, even in the absence of extrinsic stress.
Cell migration and signal transduction
Cells respond to environments and hormones with extreme accuracy and control their behaviors and metabolism in the human body. The Iijima laboratory aims to understand how cells sense extracellular chemicals through GPCRs and move toward high concentrations of chemoattractants. We also study how cells recognize insulin and regulate glucose homeostasis through tyrosine receptor kinases. We focus on intracellular signaling transduction mechanisms controlled by PI3-kinase, PTEN, mTORC2 and AKT. We use protein biochemistry, live-cell imaging, and mouse models to discover fundamental biology and translate this into the development of therapeutic interventions for human diseases, such as cancer and diabetes.
Molecular Cell (2021)
AKT is a serine/threonine kinase that plays an important role in metabolism, cell growth, and cytoskeletal dynamics. AKT is activated by two kinases, PDK1 and mTORC2. While the regulation of PDK1 is well understood, the mechanism that controls mTORC2 is unknown. By investigating insulin receptor signaling in human cells and biochemical reconstitution, we found that insulin induces the activation of mTORC2 toward AKT by assembling a supercomplex with KRAS4B and RHOA GTPases — termed KARATE (KRAS4B-RHOA-mTORC2 Ensemble). Insulin-induced KARATE assembly is controlled via phosphorylation of GTP-bound KRAS4B at S181 and GDP-bound RHOA at S188 by protein kinase A. By developing a KARATE inhibitor, we demonstrate that KRAS4B-RHOA interaction drives KARATE formation. In adipocytes, KARATE controls insulin-dependent translocation of the glucose transporter GLUT4 to the plasma membrane for glucose uptake. Thus, our work reveals a fundamental mechanism that activates mTORC2 toward AKT in insulin-regulated glucose homeostasis.
Cell Reports (2025)
This study investigates the role of the small GTPase RHOA in invasive cell migration within diverse 3D extracellular matrix (ECM) environments using non-cancerous HEK293, pancreatic cancer PANC-1, and breast cancer MDA-MB-231 cells. Spheroid invasion assays showed that RHOA loss enhanced migration in HEK293 and PANC-1 cells cultured in Geltrex but not in type I collagen. In contrast, RHOA deletion had little effect on MDA-MB-231 migration in either ECM. Enhanced migration in RHOA-deficient HEK293 cells required protein phosphatase PTP1B and the small GTPases RAC and CDC42. Unexpectedly, while RHOA knockout increased 3D migration, it reduced pancreatic tumor progression in mice. These findings reveal that RHOA regulates cell invasion in a manner dependent on ECM composition and cellular context, highlighting its complex, context-specific roles and potential as a therapeutic target in cancer.
Cell Reports (2020)
GPCR-mediated chemotactic stimulation induces hetero-oligomerization of phosphorylated GDP-bound Rho GTPase and GTP-bound Ras GTPase in directed cell migration in the social amoebae Dictyostelium discoideum. The Rho-Ras hetero-oligomers directly activate mTORC2 toward AKT. In contrast to GDP-Rho, GTP-Rho antagonizes mTORC2-AKT signaling by inhibiting the oligomerization of GDP-Rho with GTP-Ras in the back of migrating cells. Therefore, hetero-oligomerization of Rho and Ras provides a critical regulatory step that controls mTORC2-AKT signaling.
iScience (2020)
PTEN is one of the most highly mutated tumor suppressor genes. PTEN is located in the nucleus in addition to the plasma membrane. The nuclear localization of PTEN is regulated by ubiquitination of lysine 13. Nuclear PTEN suppresses DNA damage in the liver in vivo. Nuclear PTEN loss causes tumorigenesis in a mouse model for hepatocellular carcinoma.
Organelle dynamics and quality control
Mitochondria are highly dynamic: they grow, divide, and fuse in highly regulated manners. Mitochondrial division and fusion play essential roles in mitochondrial quality control to maintain this essential organelle’s health. Damaged mitochondria can be separated from healthy mitochondria by division. Fusion allows mitochondria to mix and exchange their contents. The goal of the Sesaki laboratory is to decipher the mechanisms of mitochondrial dynamics and quality control, focusing on dynamin-related GTPases, such as Drp1, Opa1, and mitofusin, as well as Parkinson’s disease proteins, Parkin and PINK1. Our approaches extend from biochemisty using purified mitochondria, proteins, and synthetic lipids to cell biology and physiology tusing super-resolution microscopy, electron microscopy, and genetically engineered mouse models.
Nature Communications (2025)
The morphology of the endoplasmic reticulum (ER), characterized by central sheets and peripheral tubules, is controlled by membrane-shaping proteins. However, the role of lipids in ER morphogenesis remains elusive, despite the ER being the major site for lipid synthesis. Here, by examining the role of eighteen phosphatidic acid (PA)-generating enzymes in ER morphology, we identify lysophosphatidic acid acyltransferase 2 (AGPAT2) as a critical factor in mouse and human cells. AGPAT2 produces PA in the glycerophospholipid/triacylglycerol biosynthesis pathway, and its mutations cause congenital generalized lipodystrophy. We find that AGPAT2-generated PA drives ER tubulation through gene knockout, 3D structural analysis by FIB-SEM, super-resolution microscopy, lipidomics, AlphaFold, and in vitro reconstitutions of ER tubulation and AGPAT2 activity. AGPAT2 interacts with and supplies PA to the PA-binding, dynamin-related GTPase, DRP1, which subsequently tubulates the ER in a manner independent of GTP hydrolysis and oligomerization, distinct from its function in mitochondrial division.
Developmental Cell (2024)
Following the Goldilocks principle, mitochondria size must be “just right.” Mitochondria balance division and fusion to avoid becoming too big or too small. Defects in this balance produce dysfunctional mitochondria in human diseases. Mitochondrial safeguard (MitoSafe) is a defense mechanism that protects mitochondria against extreme enlarging by suppressing fusion in mammalian cells. In MitoSafe, hyperfused mitochondria elicit flickering—short pulses of mitochondrial depolarization. Flickering activates an inner membrane protease, Oma1, which in turn proteolytically inactivates a mitochondrial fusion protein, Opa1. The mechanisms underlying flickering are unknown. Using a live-imaging screen, we identified Slc25a3 (a mitochondrial carrier transporting phosphate and copper) as necessary for flickering and Opa1 cleavage. Remarkably, copper, but not phosphate, is critical for flickering. Furthermore, we found that two copper-containing mitochondrial enzymes, superoxide dismutase 1 and cytochrome c oxidase, regulate flickering. Our data identify an unforeseen mechanism linking copper, redox homeostasis, and membrane flickering in mitochondrial defense against deleterious fusion.
iScience (2022)
Non-alcoholic steatohepatitis (NASH) is a most common chronic liver disease that is manifested by steatosis, inflammation, fibrosis, and tissue damage. Hepatocytes produce giant mitochondria termed megamitochondria in NASH patients. We acutely depleted OPA1, a mitochondrial dynamin-related GTPase that mediates mitochondrial fusion, using antisense oligonucleotides in a NASH mouse model before or after megamitochondria formation. When OPA1 antisense oligonucleotides were applied at the disease onset, they effectively prevented megamitochondria formation and liver pathologies in the NASH model. Notably, even when applied after mice robustly developed NASH pathologies, OPA1 targeting effectively regressed megamitochondria and the disease phenotypes. Thus, our data show the efficacy of mitochondrial dynamics as a unique therapy for megamitochondria-associated liver disease.
Molecular Cell (2020)
The mitochondria division GTPase Drp1 is associated with the ER and tubulates it independently of GTP hydrolysis. ER tubules formed by Drp1 promote mitochondrial division. Therefore, Drp1 functions as a two-in-one protein during mitochondrial division, with ER tubulation and mechano-GTPase activities.
EMBO J (2020)
The balance between membrane fusion and fission controls mitochondrial connectivity and function. Here, short pulses of membrane depolarization are found to drive an Oma1‐dependent stress response termed ‘mitochondrial safeguard’ that protects mitochondrial function upon increased mitochondrial connectivity.