Hiroko P. Indo

Mitochondria are essential organelles for cellular energy production and the regulation of diverse biological processes, including apoptosis, redox homeostasis, and intracellular signaling. Although mitochondrial reactive oxygen species (mtROS) act as critical mediators of these functions, the molecular mechanisms underlying mtROS regulation remain poorly understood. This review summarizes current insights into the role of heat shock protein 47 (HSP47) in mitochondrial oxidative stress and mtROS-mediated cellular responses. In addition to its classical function as an endoplasmic reticulum (ER) chaperone, HSP47 translocates to the mitochondria under oxidative stress conditions. This mitochondrial localization promotes mtROS production, thereby triggering apoptotic pathways and redox-sensitive signal transduction. Furthermore, we examine the mechanistic insights linking HSP47 to mitochondrial function and oxidative stress, highlighting their implications for cellular homeostasis and disease pathogenesis. Overall, these findings establish HSP47 as a novel regulator of mtROS generation, suggesting that the HSP47–mtROS axis represents a promising therapeutic target for oxidative stress-related disorders and a potential role for exploring virus-induced cellular responses in future research.

Atherosclerosis is a persistent inflammatory disorder influenced by oxidative stress and lipid imbalances, and it continues to be a major contributor to cardiovascular diseases. Rich in catechins and flavonoids, green tea pressurized hot water extract (GPHWE) demonstrated potent antioxidant activity through DPPH, ABTS, hydroxyl, and nitric oxide scavenging assays. In vitro, GPHWE protected RAW264.7 macrophages from oxidized LDL (Ox-LDL)-induced cytotoxicity and apoptosis by mitigating oxidative stress and enhancing cell survival. Animal studies using mice fed a high-fat diet (HFD) revealed notable improvements in lipid profiles, including decreases in total cholesterol, LDL, the atherosclerosis index (AI), the coronary risk index (CRI), and triglycerides, as well as lower levels of malondialdehyde (MDA), an indicator of oxidative stress. These results were comparable to those achieved with Simvastatin. Molecular docking studies indicated strong binding affinities of catechins to essential targets such as LOX-1, HMG-CoA reductase, caspase-3, and Nrf2, implying that the mechanisms of GPHWE involve antioxidant properties, regulation of lipids, and stabilization of plaques. The catechins of GPHWE, including epigallocatechin gallate (EGCG), epicatechin gallate (ECG), and epigallocatechin (EGC), were tentatively identified through qualitative analysis performed by UHPLC-QTOF-MS. This comprehensive approach positions GPHWE as a promising natural remedy for preventing atherosclerosis and reducing cardiovascular risk.

Synephrine, a protoalkaloid found in Citrus aurantium (CA) peels, exerts lipolytic, anti-inflammatory, and vasoconstrictive effects; however, its antioxidant activity remains unclear. In this study, electron spin resonance spectroscopy revealed that synephrine scavenged both hydroxyl and superoxide anion radicals. Several external stimuli, such as H₂O₂, X-rays, and ultraviolet (UV) radiation, cause stress-induced premature senescence (SIPS). As oxidative stress induces SIPS, we hypothesized that synephrine, an antioxidant, would suppress H₂O₂-induced premature senescence in WI-38 cells. Synephrine significantly decreased the reactive oxygen species levels induced by H₂O₂, thereby reducing lipid peroxidation, and oxidative DNA damage and preventing SIPS. Additionally, synephrine inhibited mitochondrial dysfunction in H₂O₂-treated WI-38 cells. The expression levels of p53, p21, and p16^-INK4A, which are involved in the induction of cell cycle arrest in SIPS, were significantly lower in synephrine-treated cells than in untreated cells. Our results indicate that synephrine inhibits H₂O₂-induced oxidative stress and mitochondrial dysfunction, suppressing premature senescence by inhibiting activation of the p53–p21 and p16^-INK4A–pRB pathways.

The universe began 13.8 billion years ago, and Earth was born 4.6 billion years ago. Early traces of life were found as soon as 4.1 billion years ago; then, ~200,000 years ago, the human being was born. The evolution of life on earth was to become individual rather than cellular life. The birth of mitochondria made this possible to be the individual life. Since then, individuals have had a limited time of life. It was 1.4 billion years ago that a bacterial cell began living inside an archaeal host cell, a form of endosymbiosis that is the development of eukaryotic cells, which contain a nucleus and other membrane-bound compartments. The bacterium started to provide its host cell with additional energy, and the interaction eventually resulted in a eukaryotic cell, with both archaeal (the host cell) and bacterial (mitochondrial) origins still having genomes. The cells survived high concentrations of oxygen producing more energy inside the cell. Further, the roles of mitochondria in human being’s life and aging will be discussed.

Questions about which reactive oxygen species (ROS) or reactive nitrogen species (RNS) can escape from the mitochondria and activate signals must be addressed. In this study, two parameters, the calculated dipole moment (debye, D) and permeability coefficient (Pm) (cm s⁻¹), are listed for hydrogen peroxide (H₂O₂), hydroxyl radical (•OH), superoxide (O₂^•−), hydroperoxyl radical (HO₂•), nitric oxide (•NO), nitrogen dioxide (•NO₂), peroxynitrite (ONOO⁻), and peroxynitrous acid (ONOOH) in comparison to those for water (H₂O). O₂^•− is generated from the mitochondrial electron transport chain (ETC), and several other ROS and RNS can be generated subsequently. The candidates which pass through the mitochondrial membrane include ROS with a small number of dipoles, i.e., H₂O₂, HO₂•, ONOOH, •OH, and •NO. The results show that the dipole moment of •NO₂ is 0.35 D, indicating permeability; however, •NO₂ can be eliminated quickly. The dipole moments of •OH (1.67 D) and ONOOH (1.77 D) indicate that they might be permeable. This study also suggests that the mitochondria play a central role in protecting against further oxidative stress in cells. The amounts, the long half-life, the diffusion distance, the Pm, the one-electron reduction potential, the pK_a, and the rate constants for the reaction with ascorbate and glutathione are listed for various ROS/RNS, •OH, singlet oxygen (¹O₂), H₂O₂, O₂^•−, HO₂•, •NO, •NO₂, ONOO⁻, and ONOOH, and compared with those for H₂O and oxygen (O₂). Molecules with negative electrical charges cannot directly diffuse through the phospholipid bilayer of the mitochondrial membranes. Short-lived molecules, such as •OH, would be difficult to contribute to intracellular signaling. Finally, HO₂• and ONOOH were selected as candidates for the ROS/RNS that pass through the mitochondrial membrane.

The effects of long-term low-dose X-ray irradiation on the outer root sheath (ORS) cells of C3H/He mice were investigated. Mice were irradiated with a regime of 100 mGy/day, 5 days/ week, for 12 weeks (Group X) and the results obtained were compared to those in a non-irradiated control (Group C). Potential protection against ORS cells damage induced by this exposure was investigated by adding the stable nitroxide radical 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) at 1 mM to the drinking water of mice (Group X + TEMPOL). The results obtained were compared with Group C and a nonirradiated group treated with TEMPOL (Group C + TEMPOL). After fractionated X-ray irradiation, skin was removed and ORS cells were examined by hematoxylin and eosin staining and electron microscopy for an abnormal nuclear morphology and nuclear condensation changes. Fractionated X-irradiated mice had an increased number of ORS cells with an abnormal nuclear morphology as well as nuclear condensation changes. Sections were also immunohistochemically examined for the presence of TdT-mediated dUTP nick-end labeling (TUNEL), 8-hydroxy-2′-deoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE), vascular endothelial growth factor (VEGF), nitrotyrosine, heme oxygenase 1 (HO-1), and protein gene product 9.5 (PGP 9.5). Significant increases were observed in TUNEL, 8-OHdG, and 4-HNE levels in ORS cells from mice in Group X. Electron microscopy also showed irregular shrunken ORS cells in Group X. These changes were prevented by the presence of TEMPOL in the drinking water of the irradiated mice. TEMPOL alone had no significant effects. These results suggest that fractionated doses of radiation induced oxidative damage in ORS cells; however, TEMPOL provided protection against this damage, possibly as a result of the rapid reaction of this nitroxide radical with the reactive oxidants generated by fractionated X-ray irradiation.

Significance: This review discusses the coronavirus disease 2019 (COVID-19) pathophysiology in the context of diabetes and intracellular reactions by COVID-19, including mitochondrial oxidative stress storms, mitochondrial ROS storms, and long COVID.Recent advances: The long COVID is suffered in ~10% of the COVID-19 patients. Even the virus does not exist, the patients suffer the long COVID for even over a year, This disease could be a mitochondria dysregulation disease.Critical issues: Patients who recover from COVID-19 can develop new or persistent symptoms of multi-organ complications lasting weeks or months, called long COVID. The underlying mechanisms involved in the long COVID is still unclear. Once the symptoms of long COVID persist, they cause significant damage, leading to numerous, persistent symptoms.Future directions: A comprehensive map of the stages and pathogenetic mechanisms related to long COVID and effective drugs to treat and prevent it are required, which will aid the development of future long COVID treatments and symptom relief.

It has been known that reactive oxygen species (ROS) are generated from the mitochondrial electron transport chain (ETC). Majima et al. proved that mitochondrial ROS (mtROS) caused apoptosis for the first time in 1998 (Majima et al. J Biol Chem, 1998). It is speculated that mtROS can move out of the mitochondria and initiate cellular signals in the nucleus. This paper aims to prove this phenomenon by assessing the change in the amount of manganese superoxide dismutase (MnSOD) by MnSOD transfection. Two cell lines of the same genetic background, of which generation of mtROS are different, i.e., the mtROS are more produced in RGK1, than in that of RGM1, were compared to analyze the cellular signals. The results of immunocytochemistry staining showed increase of Nrf2, Keap1, HO-1 and 2, MnSOD, GCL, GST, NQO1, GATA1, GATA3, GATA4, and GATA5 in RGK1 compared to those in RGM1. Transfection of human MnSOD in RGK1 cells showed a decrease of those signal proteins, suggesting mtROS play a role in cellular signals in nucleus.