Mitochondrial Communications最新文献

While it has been shown that Ca²⁺ dynamics at the ER membrane is essential for the initiation of certain types of autophagy such as starvation-induced autophagy, how mitochondrial Ca²⁺ transport changes during the first stage of autophagy is not systemically characterized. An investigation of mitochondrial Ca²⁺ dynamics during autophagy initiation may help us determine the relationship between autophagy and mitochondrial Ca²⁺ fluxes. Here we examine acute mitochondrial and ER calcium responses to a panel of autophagy inducers in different cell types. Mitochondrial Ca²⁺ transport and Ca²⁺ transients at the ER membrane are triggered by different autophagy inducers. The mitophagy-inducer-initiated mitochondrial Ca²⁺ uptake relies on mitochondrial calcium uniporter and may decelerate the following mitophagy. In neurons derived from a Parkinson's patient, mitophagy-inducer-triggered mitochondrial Ca²⁺ influx is faster, which may slow the ensuing mitophagy.

Bcl-2 and Bax share a similar structural fold in solution, yet function oppositely in the mitochondrial outer membrane (MOM) during apoptosis. The proapoptotic Bax forms pores in the MOM to trigger cell death, whereas Bcl-2 inhibits the Bax pore formation to prevent cell death. Intriguingly both proteins can switch to a similar conformation after activation by BH3-only proteins, with multiple regions embedded in the MOM. Here we tested a hypothesis that destabilization of the Bcl-2 structure might convert Bcl-2 to a Bax-like perforator. We discovered that mutations of glutamate 152 which eliminate hydrogen bonds in the protein core and thereby reduce the Bcl-2 structural stability. These Bcl-2 mutants induced apoptosis by releasing cytochrome c from the mitochondria in the cells that lack Bax and Bak, the other proapoptotic perforator. Using liposomal membranes made with typical mitochondrial lipids and reconstituted with purified proteins we revealed this perforation activity was intrinsic to Bcl-2 and could be unleashed by a BH3-only protein, similar to the perforation activity of Bax. Our study thus demonstrated a structural conversion of antiapoptotic Bcl-2 to a proapoptotic perforator through a simple molecular manipulation or interaction that is worthy to explore further for eradicating cancer cells that are resistant to a current Bcl-2-targeting drug.

The Japanese Society for Mitochondrial Research and Medicine (J-mit) has a 21-year history in 2022, with its predecessor society holding its first meeting in 2001. During this time, the society, which began as a basic researcher's society with 50 participants in the first year, has grown to have approximately 250 members, including basic medical researchers, scientists, students in graduate school, and specialists in pediatric neurology, neurology, endocrinology, and inborn errors of metabolism. The number of abstracts presented each year also exceeds 200, including symposia, educational lectures, general oral presentations, and poster presentations. This society has grown significantly, including a joint meeting with Asian Society of Mitochondrial Research and Medicine (ASMRM) once every four years. In this issue, I introduce the history of J-mit development, together with ASMRM based on deep connections. I also pick up the representative world-class achievements of Japanese researchers in mitochondrial research and medicine will be introduced.

The transmembrane-electrostatically localized protons (TELP) theory may represent a complementary development to Mitchell's chemiosmotic theory. The combination of the two together can now excellently explain the energetics in mitochondria. My calculated transmembrane-attractive force between an excess proton and an excess hydroxide explains how TELP may stay within a 1-nm thin layer at the liquid-membrane interface. Consequently, any pH sensor (sEcGFP) located at least 2–3 nm away from the membrane surface will not be able to see TELP. This feature as predicted from the TELP model was observed exactly in the experiment of Rieger et al., 2021. In contrast to their belief “the Δp at ATP synthase is almost negligible under OXPHOS conditions”, I find, when TELP activity is included in the energy calculations, there is plenty of total protonic Gibbs free energy ($\Delta G_T$) well above the physiologically required value of −24.5 kJ mol⁻¹ to drive ATP synthesis through F_oF₁-ATP synthase.

Exercise is potent stimulus for mitochondrial adaptations, serving to activate mitochondrial biogenesis as well as mitochondrial turnover. Through the process of mitophagy, dysfunctional mitochondria are selectively targeted and recycled via the lysosomes, which is activated following a single bout of exercise. The microphthalamia (MiT) family of transcription factors, including TFEB and TFE3, are widely recognized as the master regulators of lysosomal biogenesis, as they homo- and hetero-dimerize to transcriptionally regulate lysosomal and macroautophagy-related genes. It is currently unknown to what extent TFEB and TFE3 regulate mitophagy, and whether these transcription factors mediate mitochondrial adaptations to contractile activity (CA). Here we show that following an acute bout of contractile activity in cultured C2C12 murine skeletal muscle myotubes, LC3-II mitophagy flux is induced and the absence of TFEB or TFE3 impairs this acute mitophagic response. However, the loss of either transcription factor alone does not mitigate the improvements in oxygen consumption seen following chronic contractile activity (CCA). Chronic contractile activity also elicited functional improvements in lysosomes including a reduction in size and increased proteolytic activity, evidenced by increased digestion and unquenching of DQ-BSA fluorophore, thereby illustrating a level of redundancy between the two transcription factors in mediating chronic contractile activity-induced adaptations. However, in the absence of both TFEB and TFE3, lysosomal adaptations were not observed following chronic contractile activity and subsequent mitochondrial adaptations were attenuated. These findings underscore the importance of the lysosomes, and of TFEB and TFE3, in mediating mitochondrial adaptations to chronic contractile activity.

Mitochondrial dynamics are closely related to various cellular physiological activities, including cell proliferation, homeostasis, and cell migration, and are regulated by a variety of enzymes, proteins and cytokines. Abnormal mitochondrial dynamics have been identified in multiple diseases, such as Charcot-Marie-Tooth type 2A, Parkinson's disease, Alzheimer's disease and cancer. A small fraction of these diseases can be treated by targeting drugs that correct unbalanced mitochondrial dynamics. Further in-depth research into mitochondrial dynamics is significant to helping us better understand the pathogenesis of these diseases, leading to the development of targeted drugs to halt the progression of the disease and even cure it completely. In this review, we discuss primary aspects of mitochondrial dynamics, alterations in mitochondrial dynamics under stress, and abnormities in mitochondrial dynamics that promote diseases. We look forward to exploring the regulation of mitochondrial dynamics, which will provide new ideas for treating those diseases in the future.