bims-mikwok 2023-12-31 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2023‒12‒31
twelve papers selected by
Gavin McStay, Liverpool John Moores University

Neither too much nor too little: mitochondrial calcium concentration as a balance between physiological and pathological conditions.
A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass.
Inhibition of USP30 Promotes Mitophagy by Regulating Ubiquitination of MFN2 by Parkin to Attenuate Early Brain Injury After SAH.
The role of mitochondrial dynamics in disease.
Mitophagy Decreases in the Peripheral Vestibular System of Aged C57BL/6J Mice.
Mitofusin-2 Regulates Platelet Mitochondria and Function.
Therapeutic effects of the combination of moderate-intensity endurance training and MitoQ supplementation in rats with isoproterenol-induced myocardial injury: The role of mitochondrial fusion, fission, and mitophagy.
Tofacitinib restores psoriatic arthritis fibroblast-like synoviocytes function via autophagy and mitochondrial quality control modulation.
Letter to the Editor: Intratumor fibrotic HCC, a subtype matching the Hoshida S1 subclass?
Regulation of respiratory complex I assembly by FMN cofactor targeting.
p32/OPA1 axis-mediated mitochondrial dynamics contributes to cisplatin resistance in non-small cell lung cancer.
TMEM135 maintains the equilibrium of osteogenesis and adipogenesis by regulating mitochondrial dynamics.

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
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
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
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
In Vivo. 2024 Jan-Feb;38(1):38(1): 196-204

Mitophagy Decreases in the Peripheral Vestibular System of Aged C57BL/6J Mice.

Sung Il Cho, Eu-Ri Jo, Suhyun Lee.

  BACKGROUND/AIM: Mitophagy is a cardinal process for maintaining healthy and functional mitochondria. A decline in mitophagy has been associated with age-related pathologies. We aimed to investigate mitophagy changes in age-related balance problems using an animal model.MATERIALS AND METHODS: C57BL/6J mice were divided into young (1 month old) and aged (12 months old) groups. Balance performance, mitochondrial DNA integrity, ATP content, mitophagic process, and mitophagy-related genes and proteins were investigated in both groups.
RESULTS: Balance and motor performance were reduced in the aged group. Mitochondrial DNA integrity and ATP content, and mRNA levels of PINK1, Parkin, BNIP3, AMBRA1, MUL1, NIX, Bcl2-L-13, Atg3, Atg5, Atg12, and Atg13 in the vestibule were significantly lower in aged mice compared with those in young mice. The protein levels of PINK1, Parkin, BNIP3, LC3B, and OXPHOS subunits were significantly decreased in the aged vestibule. Mitophagosome and mitophagolysosome counts and the immunohistochemical expression of Parkin and BNIP3 were also decreased in the saccule, utricle, and crista ampullaris in the aged group.
CONCLUSION: A general decrease in mitophagy with aging might be attributed to a decrease in cellular function in the aged vestibule during the development of age-related balance problems.

Keywords:  Mitophagy; aging; mice; vestibular system

DOI:  https://doi.org/10.21873/invivo.13426
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
Biomed Pharmacother. 2023 Dec 25. pii: S0753-3322(23)01818-8. [Epub ahead of print]170 116020

Therapeutic effects of the combination of moderate-intensity endurance training and MitoQ supplementation in rats with isoproterenol-induced myocardial injury: The role of mitochondrial fusion, fission, and mitophagy.

Farzaneh Rostamzadeh, Hamid Najafipour, Soheil Aminizadeh, Elham Jafari.

  INTRODUCTION: Mitochondrial dysfunction causes myocardial disease. This study investigated the effects of MitoQ alone and in combination with moderate-intensity endurance training (EX) on cardiac function and content and mRNA expression of several proteins involved in mitochondrial quality control in isoproterenol (ISO)-induced heart injuries METHODS: Seven groups of CTL, ISO, ISO-EX, ISO-MitoQ-125, ISO-MitoQ-250, ISO-EX+MitoQ-125, and ISO-EX+MitoQ-250 were assigned. Rats were trained on a treadmill, and the MitoQ groups received MitoQ in drinking water for 8 weeks, starting one week after the induction of heart injury. Arterial pressure and cardiac function indices, mRNA expression, protein content, oxidant and antioxidant markers, fibrosis, and histopathological changes were assessed by physiograph, Real-Time PCR, immunofluorescence, calorimetry, Masson's trichrome, and H&E staining, respectively.RESULTS: The impacts of MitoQ-125, EX+MitoQ-125, and EX+MitoQ-250 on arterial pressure and left ventricular systolic pressure were higher than MitoQ-250 or EX alone. ± dp/dt max were higher in ISO-EX+MitoQ-125 and ISO-EX+MitoQ-250 than ISO-MitoQ-125 and ISO-MitoQ-250 groups, respectively. Histopathological scores and fibrosis decreased in ISO-EX, ISO-MitoQ-125, ISO-EX+MitoQ-125, and ISO-EX+MitoQ-250 groups. The restoration of MFN2, PINK-1, and FIS-1 changes was higher in ISO-EX+MitoQ-125 and ISO-EX+MitoQ-250 than ISO-EX, ISO-MitoQ-125 and ISO-MitoQ-250 groups. The expression of MFN2 and PINK-1 was lower in ISO-MitoQ-125 and ISO-EX+MitoQ-125 than ISO and CTL groups. The expression of FIS-1 in ISO-EX and ISO-EX+MitoQ-250 increased compared to CTL and ISO groups. MDA decreased in ISO-MitoQ-125 and ISO-EX+MitoQ-125 groups.
CONCLUSION: Exercise and MitoQ combination have additive effects on cardiac function by modulating cardiac mitochondria quality. This study provided a possible therapy to treat heart injuries.

Keywords:  Cardiac injuries; Endurance training; Fission; Fusion; MitoQ; Mitochondria

DOI:  https://doi.org/10.1016/j.biopha.2023.116020
J Autoimmun. 2023 Dec 22. pii: S0896-8411(23)00168-3. [Epub ahead of print]143 103159

Tofacitinib restores psoriatic arthritis fibroblast-like synoviocytes function via autophagy and mitochondrial quality control modulation.

Ettore Silvagni, Sonia Missiroli, Simone Patergnani, Caterina Boncompagni, Clotilde D'Ugo, Carlo Garaffoni, Maria Sofia Ciliento, Giovanni Lanza, Massimo Bonora, Roberta Gafà, Mariasole Perrone, Alessandra Bortoluzzi, Carlotta Giorgi, Marcello Govoni, Carlo Alberto Scirè, Paolo Pinton.

  OBJECTIVES: To evaluate the in vitro effect of tofacitinib on autophagy activity of psoriatic arthritis (PsA) fibroblast-like synoviocytes (FLS), and to confirm its activity on inflammatory and invasive properties of FLS and synovial cells, deepening the impact on mitochondrial function.METHODS: FLS, peripheral blood mononuclear cells (PBMCs), and synovial cells from active PsA patients were cultured with tofacitinib 1 μM or vehicle control for 24 h. Autophagy was measured by Western blot and by fluorescence microscopy. Chemokines/cytokines released into culture supernatants were quantified by ELISA, while invasive properties of FLS by migration assays. Specific mitochondrial probes were adopted to measure intracellular reactive oxygen species (ROS), mitochondrial potential, morphology, turnover and mitophagy. Oxygen consumption rate (OCR), reflecting oxidative phosphorylation, was quantified using the Seahorse technology. Differences were determined by adopting the non-parametric Wilcoxon signed rank test.
RESULTS: 18 patients with moderately-to-severely active PsA were enrolled. Tofacitinib significantly increased the levels of the autophagy markers LC3-II and ATG7 in PsA FLS compared to vehicle control, suggesting an increase in spontaneous autophagy activity; no effect was highlighted in PBMCs and synovial cells cultures. Tofacitinib reduced migration properties of PsA FLS, and reduced MCP-1 and IL-6 release into FLS and synovial cells cultures supernatants. Furthermore, tofacitinib decreased intracellular ROS production, increased basal OCR, ATP production and maximal respiratory capacity, and enhanced mitophagy and mitochondrial turnover.
CONCLUSIONS: The JAK inhibitor tofacitinib reduces the pro-invasive and pro-inflammatory properties of PsA FLS. Autophagy induction and mitochondrial quality control modulation by tofacitinib might contribute to FLS function restoration.

Keywords:  Autophagy; Fibroblast-like synoviocytes; Mitochondrial function; Psoriatic arthritis; Tofacitinib

DOI:  https://doi.org/10.1016/j.jaut.2023.103159
Hepatology. 2023 Dec 25.

Letter to the Editor: Intratumor fibrotic HCC, a subtype matching the Hoshida S1 subclass?

Tian-Cheng Wang, Yu-Dong Xiao, Peng Zhou.

DOI: https://doi.org/10.1097/HEP.0000000000000736
Redox Biol. 2023 Dec 20. pii: S2213-2317(23)00402-0. [Epub ahead of print]69 103001

Regulation of respiratory complex I assembly by FMN cofactor targeting.

Andrea Curtabbi, Adela Guarás, José Luis Cabrera-Alarcón, Maribel Rivero, Enrique Calvo, Marina Rosa-Moreno, Jesús Vázquez, Milagros Medina, José Antonio Enríquez.

  Respiratory complex I plays a crucial role in the mitochondrial electron transport chain and shows promise as a therapeutic target for various human diseases. While most studies focus on inhibiting complex I at the Q-site, little is known about inhibitors targeting other sites within the complex. In this study, we demonstrate that diphenyleneiodonium (DPI), a N-site inhibitor, uniquely affects the stability of complex I by reacting with its flavin cofactor FMN. Treatment with DPI blocks the final stage of complex I assembly, leading to the complete and reversible degradation of complex I in different cellular models. Growing cells in medium lacking the FMN precursor riboflavin or knocking out the mitochondrial flavin carrier gene SLC25A32 results in a similar complex I degradation. Overall, our findings establish a direct connection between mitochondrial flavin homeostasis and complex I stability and assembly, paving the way for novel pharmacological strategies to regulate respiratory complex I.

Keywords:  DPI; FMN; OXPHOS; Respiratory complex I

DOI:  https://doi.org/10.1016/j.redox.2023.103001
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
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