bims-midtic 2023-12-31 papers

bims-midtic

Biomed News

on Mitochondrial dynamics and trafficking in cells

Issue of 2023‒12‒31
sixteen papers selected by
Omkar Joshi, Turku Bioscience

The role of mitochondrial dynamics in disease.
Interactome analysis identifies the role of BZW2 in promoting endoplasmic reticulum-mitochondrial contact and mitochondrial metabolism.
TMEM135 maintains the equilibrium of osteogenesis and adipogenesis by regulating mitochondrial dynamics.
Effect of apigenin on dynamin-related protein 1 in type 1 diabetic rats with cardiovascular complications.
p32/OPA1 axis-mediated mitochondrial dynamics contributes to cisplatin resistance in non-small cell lung cancer.
Inhibition of USP30 Promotes Mitophagy by Regulating Ubiquitination of MFN2 by Parkin to Attenuate Early Brain Injury After SAH.
Mitochondrial-regulated Tregs: potential therapeutic targets for autoimmune diseases of the central nervous system.
A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass.
Heptamethine Cyanine-Based Molecule Release Triggered by Mitochondrial ROS.
Obesity-induced PARIS (ZNF746) accumulation in adipose progenitor cells leads to attenuated mitochondrial biogenesis and impaired adipogenesis.
Mitofusin-2 induced by exercise modifies lipid droplet-mitochondria communication, promoting fatty acid oxidation in male mice with NAFLD.
Guanxin V alleviates ventricular remodeling after acute myocardial infarction with circadian disruption by regulating mitochondrial dynamics.
Mitofusin-2 Regulates Platelet Mitochondria and Function.
Mitochondrion: Main organelle in orchestrating cancer escape from chemotherapy.
Neither too much nor too little: mitochondrial calcium concentration as a balance between physiological and pathological conditions.
Prohibitin 2: A key regulator of cell function.

MedComm (2020). 2023 Dec;4(6): e462

The role of mitochondrial dynamics in disease.

Yujuan Wang, Xinyan Dai, Hui Li, Huiling Jiang, Junfu Zhou, Shiying Zhang, Jiacheng Guo, Lidu Shen, Huantao Yang, Jie Lin, Hengxiu Yan.

  Mitochondria are multifaceted and dynamic organelles regulating various important cellular processes from signal transduction to determining cell fate. As dynamic properties of mitochondria, fusion and fission accompanied with mitophagy, undergo constant changes in number and morphology to sustain mitochondrial homeostasis in response to cell context changes. Thus, the dysregulation of mitochondrial dynamics and mitophagy is unsurprisingly related with various diseases, but the unclear underlying mechanism hinders their clinical application. In this review, we summarize the recent developments in the molecular mechanism of mitochondrial dynamics and mitophagy, particularly the different roles of key components in mitochondrial dynamics in different context. We also summarize the roles of mitochondrial dynamics and target treatment in diseases related to the cardiovascular system, nervous system, respiratory system, and tumor cell metabolism demanding high-energy. In these diseases, it is common that excessive mitochondrial fission is dominant and accompanied by impaired fusion and mitophagy. But there have been many conflicting findings about them recently, which are specifically highlighted in this view. We look forward that these findings will help broaden our understanding of the roles of the mitochondrial dynamics in diseases and will be beneficial to the discovery of novel selective therapeutic targets.

Keywords:  context; disease; mitochondrial dynamics; mitophagy; target treatment

DOI:  https://doi.org/10.1002/mco2.462
Mol Cell Proteomics. 2023 Dec 26. pii: S1535-9476(23)00220-7. [Epub ahead of print] 100709

Interactome analysis identifies the role of BZW2 in promoting endoplasmic reticulum-mitochondrial contact and mitochondrial metabolism.

George Maio, Mike Smith, Ruchika Bhawal, Sheng Zhang, Jeremy M Baskin, Jenny Li, Hening Lin.

Understanding the molecular functions of less-studied proteins is an important task of life science research. Despite reports of BZW2 (Basic leucine zipper and W2 domain-containing protein 2) promoting cancer progression first emerging in 2017, little is known about its molecular function. Using a quantitative proteomic approach to identify its interacting proteins, we found that BZW2 interacts with both endoplasmic reticulum (ER) and mitochondrial proteins. We thus hypothesized that BZW2 localizes to and promotes the formation of ER-mitochondrial contact sites, and that such localization would promote calcium transport from ER to the mitochondria and promote ATP production. Indeed, we found that BZW2 localized to ER-mitochondria contact sites and that BZW2 knockdown decreased ER-mitochondrial contact, mitochondrial calcium levels, and ATP production. These findings provide key insights into molecular functions of BZW2, the potential role of BZW2 in cancer progression, and highlight the utility of interactome data in understanding the function of less-studied proteins.

DOI: https://doi.org/10.1016/j.mcpro.2023.100709
Metabolism. 2023 Dec 26. pii: S0026-0495(23)00371-2. [Epub ahead of print] 155767

TMEM135 maintains the equilibrium of osteogenesis and adipogenesis by regulating mitochondrial dynamics.

Jia Liu, Xiaogang Bao, Jian Huang, Rukun Chen, Yixuan Tan, Zheng Zhang, Bing Xiao, Fanqi Kong, Changjiang Gu, Jianhang Du, Haotian Wang, Junqiang Qi, Junming Tan, Duan Ma, Changgui Shi, Guohua Xu.

  BACKGROUND: Disturbance in the differentiation process of bone marrow mesenchymal stem cells (BMSCs) leads to osteoporosis. Mitochondrial dynamics plays a pivotal role in the metabolism and differentiation of BMSCs. However, the mechanisms underlying mitochondrial dynamics and their impact on the differentiation equilibrium of BMSCs remain unclear.METHODS: We investigated the mitochondrial morphology and markers related to mitochondrial dynamics during BMSCs osteogenic and adipogenic differentiation. Bioinformatics was used to screen potential genes regulating BMSCs differentiation through mitochondrial dynamics. Subsequently, we evaluated the impact of Transmembrane protein 135 (TMEM135) deficiency on bone homeostasis by comparing Tmem135 knockout mice with their littermates. The mechanism of TMEM135 in mitochondrial dynamics and BMSCs differentiation was also investigated in vivo and in vitro.
RESULTS: Distinct changes in mitochondrial morphology were observed between osteogenic and adipogenic differentiation of BMSCs, manifesting as fission in the late stage of osteogenesis and fusion in adipogenesis. Additionally, we revealed that TMEM135, a modulator of mitochondrial dynamics, played a functional role in regulating the equilibrium between adipogenesis and osteogenesis. The TMEM135 deficiency impaired mitochondrial fission and disrupted crucial mitochondrial energy metabolism during osteogenesis. Tmem135 knockout mice showed osteoporotic phenotype, characterized by reduced osteogenesis and increased adipogenesis. Mechanistically, TMEM135 maintained intracellular calcium ion homeostasis and facilitated the dephosphorylation of dynamic-related protein 1 at Serine 637 in BMSCs.
CONCLUSIONS: Our findings underscore the significant role of TMEM135 as a modulator in orchestrating the differentiation trajectory of BMSCs and promoting a shift in mitochondrial dynamics toward fission. This ultimately contributes to the osteogenesis process. This work has provided promising biological targets for the treatment of osteoporosis.

Keywords:  Adipogenesis; Energy metabolism; Mitochondrial dynamics; Osteogenesis; Osteoporosis; Transmembrane proteins

DOI:  https://doi.org/10.1016/j.metabol.2023.155767
Gene. 2023 Dec 21. pii: S0378-1119(23)00948-4. [Epub ahead of print] 148107

Effect of apigenin on dynamin-related protein 1 in type 1 diabetic rats with cardiovascular complications.

Sara Gamal Sherif, Marwa Tarek, Yasmine Gamal Sabry, Azza Hassan Abou Ghalia.

  BACKGROUND AND OBJECTIVE: Cardiovascular complications cause increased mortality rates among diabetics. The molecular mechanisms of aberrant mitochondrial dynamics in diabetes mellitus (DM) are not fully understood. Dynamin-related protein 1 (Drp1) is thought to be a major regulator of mitochondrial fission. There is lack of studies that examined the relationship between apigenin and Drp1 expression in DM. thus, the current study aimed to explore the expression of Drp1 in diabetic rats with cardiovascular complications, as well as to appraise the role of apigenin in modulating this expression.METHODS: Twenty-eight adult male albino Wister rats were randomly and equally allocated into four groups: naive, streptozotocin-induced type 1 diabetic control and two apigenin-injected diabetic groups (early and late). Body weight, heart weight, blood pressure and ECG were recorded. Evaluation of blood glucose level, lipid profile and cardiac functions were measured. Determination of Drp1 mRNA expression, and histological examination of cardiac tissues from the four groups were performed.
RESULTS: Diabetic control rats developed decrease of body weight, increase of blood pressure, deterioration of the normal ECG pattern and upregulation of Drp1 mRNA expression in cardiac tissues. There was a significant correlation between the relative expression of Drp1 and all examined parameters. Apigenin-injection improved fasting blood glucose, lipid profile and cardiac function indicators (i.e., ECG parameters, CK-MB and troponin) as well as the cardiac histological structure. The decrease of Drp1 expression was more evident with early than with late apigenin-injection, however, without statistical significance.
CONCLUSIONS: Increased level of Drp1 expression in diabetic rats may be involved in the pathogenesis of diabetic cardiovascular complications. The changes that occurred in response to apigenin injection highlight its potential ameliorative effect on the diabetic cardiovascular complications and pave the route for further investigations.

Keywords:  Apigenin; Diabetes mellitus; Drp1; Mitochondrial fission

DOI:  https://doi.org/10.1016/j.gene.2023.148107
Acta Biochim Biophys Sin (Shanghai). 2023 Dec 27.

p32/OPA1 axis-mediated mitochondrial dynamics contributes to cisplatin resistance in non-small cell lung cancer.

Chun-Xia Yu, Zhe-Qing Peng, Tao Wang, Xin-Hui Qu, Ping Yang, Shao-Rong Huang, Li-Ping Jiang, Fang-Fang Tou, Xiao-Jian Han.

  Cisplatin resistance is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). p32 and OPA1 are the key regulators of mitochondrial morphology and function. This study aims to investigate the role of the p32/OPA1 axis in cisplatin resistance in NSCLC and its underlying mechanism. The levels of p32 protein and mitochondrial fusion protein OPA1 are higher in cisplatin-resistant A549/DDP cells than in cisplatin-sensitive A549 cells, which facilitates mitochondrial fusion in A549/DDP cells. In addition, the expression of p32 and OPA1 protein is also upregulated in A549 cells during the development of cisplatin resistance. Moreover, p32 knockdown effectively downregulates the expression of OPA1, stimulates mitochondrial fission, decreases ATP generation and sensitizes A549/DDP cells to cisplatin-induced apoptosis. Furthermore, metformin significantly downregulates the expressions of p32 and OPA1 and induces mitochondrial fission and a decrease in ATP level in A549/DDP cells. The co-administration of metformin and cisplatin shows a significantly greater decrease in A549/DDP cell viability than cisplatin treatment alone. Moreover, D-erythro-Sphingosine, a potent p32 kinase activator, counteracts the metformin-induced downregulation of OPA1 and mitochondrial fission in A549/DDP cells. Taken together, these findings indicate that p32/OPA1 axis-mediated mitochondrial dynamics contributes to the acquired cisplatin resistance in NSCLC and that metformin resensitizes NSCLC to cisplatin, suggesting that targeting p32 and mitochondrial dynamics is an effective strategy for the prevention of cisplatin resistance.

Keywords:  OPA1; cisplatin resistance; metformin; mitochondrial dynamics; non-small cell lung cancer; p32

DOI:  https://doi.org/10.3724/abbs.2023247
Transl Stroke Res. 2023 Dec 26.

Inhibition of USP30 Promotes Mitophagy by Regulating Ubiquitination of MFN2 by Parkin to Attenuate Early Brain Injury After SAH.

Yang Liu, Chenbei Yao, Bin Sheng, Simin Zhi, Xiangxin Chen, Pengfei Ding, Jiatong Zhang, Zhennan Tao, Wei Li, Zong Zhuang, Jiannan Mao, Zheng Peng, Huiying Yan, Wei Jin.

  Subarachnoid hemorrhage (SAH) is a type of stroke with a high disability and mortality rate. Apoptosis caused by massive damage to mitochondria in neuron cells and inflammatory responses caused by high extracellular ATP lead to poor outcomes. USP30 is a deubiquitinating enzyme that inhibits mitophagy, resulting in a failure to remove damaged mitochondria in a timely manner after SAH; nevertheless, the pathway through which USP30 inhibits mitophagy is unknown. This study evaluated the neuroprotective role and possible molecular basis by which inhibiting USP30 to attenuate SAH-induced EBI by promoting neuronal mitophagy. We used an in vitro model of hemoglobin exposure and an in vivo model of intravascular perforation. Increased expression of USP30 was found after SAH in vivo and in vitro, and USP30 inhibition expression in SAH mice treated with MF094 resulted in significant improvement of neurological injury and inflammatory response and mediated good outcomes, suggesting a neuroprotective effect of USP30 inhibition. In cultured neurons, inhibition of USP30 promoted ubiquitination modification of mitochondrial fusion protein 2 (MFN2) by E3 ubiquitin ligase (Parkin), separating damaged mitochondria from the healthy mitochondrial network and prompting mitophagy, causing early clearance of damaged intracellular mitochondria, and reducing the onset of apoptosis. The high extracellular ATP environment was meliorated, reversing the conversion of microglia to a pro-inflammatory phenotype and reducing inflammatory injury. USP30 inhibition had no autophagy-promoting effect on structurally and functionally sound mitochondria and did not inhibit normal intracellular ATP production. The findings suggest that USP30 inhibition has a neuroprotective effect after SAH by promoting early mitophagy after SAH to clear damaged mitochondria.

Keywords:  MF094; Mitochondrial fusion protein 2 (MFN2); Mitophagy; Subarachnoid hemorrhage (SAH); Ubiquitin-specific protease 30 (USP30); Ubiquitination

DOI:  https://doi.org/10.1007/s12975-023-01228-3
Front Immunol. 2023 ;14 1301074

Mitochondrial-regulated Tregs: potential therapeutic targets for autoimmune diseases of the central nervous system.

Aoya Han, Tingting Peng, Yinyin Xie, Wanwan Zhang, Wenlin Sun, Yi Xie, Yunqing Ma, Cui Wang, Nanchang Xie.

  Regulatory T cells (Tregs) can eliminate autoreactive lymphocytes, induce self-tolerance, and suppress the inflammatory response. Mitochondria, as the energy factories of cells, are essential for regulating the survival, differentiation, and function of Tregs. Studies have shown that patients with autoimmune diseases of the central nervous system, such as multiple sclerosis, neuromyelitis optica spectrum disorder, and autoimmune encephalitis, have aberrant Tregs and mitochondrial damage. However, the role of mitochondrial-regulated Tregs in autoimmune diseases of the central nervous system remains inconclusive. Therefore, this study reviews the mitochondrial regulation of Tregs in autoimmune diseases of the central nervous system and investigates the possible mitochondrial therapeutic targets.

Keywords:  Foxp3; autoimmune diseases; central nervous system; mitochondria; regulatory T cell; self-tolerance

DOI:  https://doi.org/10.3389/fimmu.2023.1301074
Mol Cell. 2023 Dec 21. pii: S1097-2765(23)01014-6. [Epub ahead of print]

A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass.

Yuqiu Sun, Yu Cao, Huayun Wan, Adalet Memetimin, Yang Cao, Lin Li, Chongyang Wu, Meng Wang, She Chen, Qi Li, Yan Ma, Mengqiu Dong, Hui Jiang.

  Mitophagy mediated by BNIP3 and NIX critically regulates mitochondrial mass. Cellular BNIP3 and NIX levels are tightly controlled by SCFFBXL4-mediated ubiquitination to prevent excessive mitochondrial loss and lethal disease. Here, we report that knockout of PPTC7, a mitochondrial matrix protein, hyperactivates BNIP3-/NIX-mediated mitophagy and causes perinatal lethality that is rescued by NIX knockout in mice. Biochemically, the PPTC7 precursor is trapped by BNIP3 and NIX to the mitochondrial outer membrane, where PPTC7 scaffolds assembly of a substrate-PPTC7-SCFFBXL4 holocomplex to degrade BNIP3 and NIX, forming a homeostatic regulatory loop. PPTC7 possesses an unusually weak mitochondrial targeting sequence to facilitate its outer membrane retention and mitophagy control. Starvation upregulates PPPTC7 expression in mouse liver to repress mitophagy, which critically maintains hepatic mitochondrial mass, bioenergetics, and gluconeogenesis. Collectively, PPTC7 functions as a mitophagy sensor that integrates homeostatic and physiological signals to dynamically control BNIP3 and NIX degradation, thereby maintaining mitochondrial mass and cellular homeostasis.

Keywords:  Cullin; FBXL4; PPTC7; metabolism; mitochondrial mass; mitophagy receptors BNIP3 and NIX; ubiquitin

DOI:  https://doi.org/10.1016/j.molcel.2023.11.038
ACS Appl Bio Mater. 2023 Dec 27.

Heptamethine Cyanine-Based Molecule Release Triggered by Mitochondrial ROS.

Jing Liu, Pu Yan, Xiangjun Liu, Zhenhao Long, Tao Bing, Nan Zhang, Dihua Shangguan.

  Conditionally activated molecule release in live cells would provide spatiotemporal control for the study and intervention of biological processes, e.g., bioactive molecule monitoring and controlled drug release. Mitochondria are the main sites of reactive oxygen species (ROS) production in cells. Here, we report an ROS-triggered molecule release strategy in mitochondria. A molecule IRTO with dual targeting groups was designed by covalently linking IR-780 (a mitochondrial targeted heptamethine cyanine) and 4-aminobutyl-thiazole orange (NH2-TO, a nuclear dye). IRTO diffused into live cells and first accumulated in mitochondria. As the cyanine moiety reacted with mitochondrial ROS directly or with the help of mitochondrial cytochromes, NH2-TO was released, escaped from mitochondria, and finally located in the nucleus. This process could be visualized by fluorescent imaging, i.e., red fluorescence (from the cyanine moiety of IRTO) first located in mitochondria, and green fluorescence (from NH2-TO) appeared and gradually enhanced in the nucleus with the increase of incubation time. The addition of H2O2 or lipopolysaccharide (LPS, an ROS accelerator) could accelerate the release of NH2-TO, whereas N-acetyl-l-cysteine (NAC, an ROS inhibitor) and mitoquinone mesylate (MitoQ, a mitochondrial ROS scavenger) could obviously decrease the release of NH2-TO. These results suggest that IRTO could serve as a fluorescent probe for monitoring ROS in mitochondria and that IR-780 might be a promising endogenous ROS-triggered molecule release platform.

Keywords:  heptamethine cyanine; mitochondrial ROS; molecular probe; molecule release; thiazole orange

DOI:  https://doi.org/10.1021/acsabm.3c00955
Sci Rep. 2023 12 27. 13(1): 22990

Obesity-induced PARIS (ZNF746) accumulation in adipose progenitor cells leads to attenuated mitochondrial biogenesis and impaired adipogenesis.

Kazuki Hachiya, Yusuke Deguchi, Takuro Hirata, Tomoya Arikawa, Hiroto Fukai, Tatsuhiro Esashi, Kota Nagasawa, Yuhei Mizunoe, Yuka Nozaki, Masaki Kobayashi, Yoshikazu Higami.

White adipose tissue (WAT) is critical for whole-body energy metabolism, and its dysfunction leads to various metabolic disorders. In recent years, many studies have suggested that impaired mitochondria may contribute to obesity-related decline in adipose tissue function, but the detailed mechanisms remain unclear. To investigate these mechanisms, we carried out a comprehensive analysis of WAT from mice with diet-induced obesity. We discovered the transcription factor Parkin interactive substrate (PARIS or ZNF746), which suppresses the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a key regulator of mitochondrial biogenesis, to be accumulated in adipose progenitor cells from obese mice. Furthermore, we demonstrated that 3T3-L1 preadipocytes with overexpression of PARIS protein exhibited decreased mitochondrial biogenesis and impaired adipogenesis. Our results suggest that the accumulation of PARIS protein may be a novel component in the pathogenesis of obesity-related dysfunction in WAT.

DOI: https://doi.org/10.1038/s41598-023-49996-0
Metabolism. 2023 Dec 22. pii: S0026-0495(23)00369-4. [Epub ahead of print] 155765

Mitofusin-2 induced by exercise modifies lipid droplet-mitochondria communication, promoting fatty acid oxidation in male mice with NAFLD.

Juan Carlos Bórquez, Francisco Díaz-Castro, Francisco Pino-de La Fuente, Karla Espinoza, Ana María Figueroa, Inma Martínez-Ruíz, Vanessa Hernández, Iliana López-Soldado, Raúl Ventura, Joan Carles Domingo, Marta Bosch, Alba Fajardo, David Sebastian, Alejandra Espinosa, Albert Pol, Antonio Zorzano, Víctor Cortés, María Isabel Hernández-Alvarez, Rodrigo Troncoso.

  BACKGROUND AND AIM: The excessive accumulation of lipid droplets (LDs) is a defining characteristic of nonalcoholic fatty liver disease (NAFLD). The interaction between LDs and mitochondria is functionally important for lipid metabolism homeostasis. Exercise improves NAFLD, but it is not known if it has an effect on hepatic LD-mitochondria interactions. Here, we investigated the influence of exercise on LD-mitochondria interactions and its significance in the context of NAFLD.APPROACH AND RESULTS: Mice were fed high-fat diet (HFD) or HFD-0.1 % methionine and choline-deficient diet (MCD) to emulate simple hepatic steatosis or non-alcoholic steatohepatitis, respectively. In both models, aerobic exercise decreased the size of LDs bound to mitochondria and the number of LD-mitochondria contacts. Analysis showed that the effects of exercise on HOMA-IR and liver triglyceride levels were independent of changes in body weight, and a positive correlation was observed between the number of LD-mitochondria contacts and NAFLD severity and with the lipid droplet size bound to mitochondria. Cellular fractionation studies revealed that ATP-coupled respiration and fatty acid oxidation (FAO) were greater in hepatic peridroplet mitochondria (PDM) from HFD-fed exercised mice than from equivalent sedentary mice. Finally, exercise increased FAO and mitofusin-2 abundance exclusively in PDM through a mechanism involving the curvature of mitochondrial membranes and the abundance of saturated lipids. Accordingly, hepatic mitofusin-2 ablation prevented exercise-induced FAO in PDM.
CONCLUSIONS: This study demonstrates that aerobic exercise has beneficial effects in murine NAFLD models by lessening the interactions between hepatic LDs and mitochondria, and by decreasing LD size, correlating with a reduced severity of NAFLD. Additionally, aerobic exercise increases FAO in PDM and this process is reliant on Mfn-2 enrichment, which modifies LD-mitochondria communication.

Keywords:  Fatty acid oxidation; Hepatocytes; Mitofusin-2; Peridroplet mitochondria; Steatohepatitis

DOI:  https://doi.org/10.1016/j.metabol.2023.155765
Sleep Breath. 2023 Dec 26.

Guanxin V alleviates ventricular remodeling after acute myocardial infarction with circadian disruption by regulating mitochondrial dynamics.

Songyi Cheng, Jing Wu, Yinghao Pei, Huaqin Tong, Manlu Fan, Qian Xiang, Yuhan Ding, Liang Xie, Haowen Zhang, Weixin Sun, Xiaoxiao Zhang, Yongchun Zhu, Ning Gu.

  PURPOSE: Circadian disruption has been a common issue due to modern lifestyles. Ventricular remodeling (VR) is a pivotal progressive pathologic change after acute myocardial infarction (AMI) and circadian disruption may have a negative influence on VR according to the latest research. Whether or not Guanxin V (GXV) has a positive effect on VR after AMI with circadian disruption drew our interest.METHODS: Rats were randomly divided into a sham group, an AMI group, an AMI with circadian disruption group, and an AMI with circadian disruption treated with the GXV group according to a random number table. RNA sequencing (RNA-Seq) was utilized to confirm the different expressed genes regulated by circadian disruption. Cardiac function, inflammation factors, pathological evaluation, and mitochondrial dynamics after the intervention were conducted to reveal the mechanism by which GXV regulated VR after AMI with circadian disruption.
RESULTS: RNA-Seq demonstrated that NF-κB was up-regulated by circadian disruption in rats with AMI. Functional and pathological evaluation indicated that compared with the AMI group, circadian disruption was associcataed with deteriorated cardiac function, expanded infarcted size, and exacerbated fibrosis and cardiomyocyte apoptosis. Further investigation demonstrated that mitochondrial dynamics imbalance was induced by circadian disruption. GXV intervention reversed the inflammatory status including down-regulation of NF-κB. Reserved cardiac function, limited infarct size, and ameliorated fibrosis and apoptosis were also observed in the GXV treated group. GXV maintained mitochondrial fission/fusion imbalance through suppressed expression of mitochondrial fission-associated proteins.
CONCLUSION: The study findings suggest that identified mitochondrial dysfunctions may underlie the link between circadian disruption and VR. GXV may exert cardioprotection after AMI with circadian disruption through regulating mitochondrial dynamics.

Keywords:  Acute myocardial infarction; Circadian disruption; Guanxin V; Mitochondrial dynamics; Ventricular remodeling

DOI:  https://doi.org/10.1007/s11325-023-02974-2
Circ Res. 2023 Dec 29.

Mitofusin-2 Regulates Platelet Mitochondria and Function.

Shancy Jacob, Yasuhiro Kosaka, Seema Bhatlekar, Frederik Denorme, Haley Benzon, Alexandra Moody, Victoria Moody, Emilia Tugolukova, Grayson Hull, Nina Kishimoto, Bhanu K Manne, Li Guo, Rhonda Souvenir, Brayden J Seliger, Alicia S Eustes, Kelly Hoerger, Neal D Tolley, Amir N Fatahian, Sihem Boudina, David C Christiani, Yongyue Wei, Can Ju, Robert A Campbell, Matthew T Rondina, E Dale Abel, Paul F Bray, Andrew S Weyrich, Jesse W Rowley.

  BACKGROUND: Single-nucleotide polymorphisms linked with the rs1474868 T allele (MFN2 [mitofusin-2] T/T) in the human mitochondrial fusion protein MFN2 gene are associated with reduced platelet MFN2 RNA expression and platelet counts. This study investigates the impact of MFN2 on megakaryocyte and platelet biology.METHODS: Mice with megakaryocyte/platelet deletion of Mfn2 (Mfn2-/- [Mfn2 conditional knockout]) were generated using Pf4-Cre crossed with floxed Mfn2 mice. Human megakaryocytes were generated from cord blood and platelets isolated from healthy subjects genotyped for rs1474868. Ex vivo approaches assessed mitochondrial morphology, function, and platelet activation responses. In vivo measurements included endogenous/transfused platelet life span, tail bleed time, transient middle cerebral artery occlusion, and pulmonary vascular permeability/hemorrhage following lipopolysaccharide-induced acute lung injury.
RESULTS: Mitochondria was more fragmented in megakaryocytes derived from Mfn2-/- mice and from human cord blood with MFN2 T/T genotype compared with control megakaryocytes. Human resting platelets of MFN2 T/T genotype had reduced MFN2 protein, diminished mitochondrial membrane potential, and an increased rate of phosphatidylserine exposure during ex vivo culture. Platelet counts and platelet life span were reduced in Mfn2-/- mice accompanied by an increased rate of phosphatidylserine exposure in resting platelets, especially aged platelets, during ex vivo culture. Mfn2-/- also decreased platelet mitochondrial membrane potential (basal) and activated mitochondrial oxygen consumption rate, reactive oxygen species generation, calcium flux, platelet-neutrophil aggregate formation, and phosphatidylserine exposure following dual agonist activation. Ultimately, Mfn2-/- mice showed prolonged tail bleed times, decreased ischemic stroke infarct size after cerebral ischemia-reperfusion, and exacerbated pulmonary inflammatory hemorrhage following lipopolysaccharide-induced acute lung injury. Analysis of MFN2 SNPs in the iSPAAR study (Identification of SNPs Predisposing to Altered ALI Risk) identified a significant association between MFN2 and 28-day mortality in patients with acute respiratory distress syndrome.
CONCLUSIONS: Mfn2 preserves mitochondrial phenotypes in megakaryocytes and platelets and influences platelet life span, function, and outcomes of stroke and lung injury.

Keywords:  blood platelets; ischemic stroke; megakaryocytes; mitochondria; neutrophils

DOI:  https://doi.org/10.1161/CIRCRESAHA.123.322914
Cancer Rep (Hoboken). 2023 Dec 27. e1942

Mitochondrion: Main organelle in orchestrating cancer escape from chemotherapy.

Samaneh Mostafavi, Nahid Eskandari.

  BACKGROUND: Chemoresistance is a challenging barrier to cancer therapy, and in this context, the role of mitochondria is significant. We put emphasis on key biological characteristics of mitochondria, contributing to tumor escape from various therapies, to find the "Achilles' Heel" of cancer cells for future drug design.RECENT FINDINGS: The mitochondrion is a dynamic organelle, and its existence is important for tumor growth. Its metabolites also cooperate with cell signaling in tumor proliferation and drug resistance.
CONCLUSION: Biological characteristics of this organelle, such as redox balance, DNA depletion, and metabolic reprogramming, provide flexibility to cancer cells to cope with therapy-induced stress.

Keywords:  drug resistance; mitochondria; neoplasm; oxidation-reduction

DOI:  https://doi.org/10.1002/cnr2.1942
Front Mol Biosci. 2023 ;10 1336416

Neither too much nor too little: mitochondrial calcium concentration as a balance between physiological and pathological conditions.

Donato D'Angelo, Denis Vecellio Reane, Anna Raffaello.

  Ca2+ ions serve as pleiotropic second messengers in the cell, regulating several cellular processes. Mitochondria play a fundamental role in Ca2+ homeostasis since mitochondrial Ca2+ (mitCa2+) is a key regulator of oxidative metabolism and cell death. MitCa2+ uptake is mediated by the mitochondrial Ca2+ uniporter complex (MCUc) localized in the inner mitochondrial membrane (IMM). MitCa2+ uptake stimulates the activity of three key enzymes of the Krebs cycle, thereby modulating ATP production and promoting oxidative metabolism. As Paracelsus stated, "Dosis sola facit venenum,"in pathological conditions, mitCa2+ overload triggers the opening of the mitochondrial permeability transition pore (mPTP), enabling the release of apoptotic factors and ultimately leading to cell death. Excessive mitCa2+ accumulation is also associated with a pathological increase of reactive oxygen species (ROS). In this article, we review the precise regulation and the effectors of mitCa2+ in physiopathological processes.

Keywords:  calcium; cell death; metabolism; mitochondria; mitochondrial calcium uniporter (MCU)

DOI:  https://doi.org/10.3389/fmolb.2023.1336416
Life Sci. 2023 Dec 22. pii: S0024-3205(23)01006-8. [Epub ahead of print] 122371

Prohibitin 2: A key regulator of cell function.

Bingjie Zhang, Wentao Li, Jiaying Cao, Yanhong Zhou, Xia Yuan.

  The PHB2 gene is located on chromosome 12p13 and encodes prohibitin 2, a highly conserved protein of 37 kDa. PHB2 is a dimer with antiparallel coils, possessing a unique negatively charged region crucial for its mitochondrial molecular chaperone functions. Thus, PHB2 plays a significant role in cell life activities such as mitosis, mitochondrial autophagy, signal transduction, and cell death. This review discusses how PHB2 inhibits transcription factors or nuclear receptors to maintain normal cell functions; how PHB2 in the cytoplasm or membrane ensures normal cell mitosis and regulates cell differentiation; how PHB2 affects mitochondrial structure, function, and cell apoptosis through mitochondrial intimal integrity and mitochondrial autophagy; how PHB2 affects mitochondrial stress and inhibits cell apoptosis by regulating cytochrome c migration and other pathways; how PHB2 affects cell growth, proliferation, and metastasis through a mitochondrial independent mechanism; and how PHB2 could be applied in disease treatment. We provide a theoretical basis and an innovative perspective for a comprehensive understanding of the role and mechanism of PHB2 in cell function regulation.

Keywords:  Cell physiology; Drug targeting; Mitophagy; PHB2; Signal transduction

DOI:  https://doi.org/10.1016/j.lfs.2023.122371