bims-midtic 2024-02-11 papers

bims-midtic

Biomed News

on Mitochondrial dynamics and trafficking in cells

Issue of 2024–02–11
27 papers selected by
Omkar Joshi, Turku Bioscience

Pharmacological Activation of AMPK Prevents Drp1-mediated Mitochondrial Fission and Alleviates Hepatic Steatosis In vitro.
Super-resolution microscopies, technological breakthrough to decipher mitochondrial structure and dynamic.
Navigating the landscape of mitochondrial-ER communication in health and disease.
Remodelling of mitochondrial function by import of specific lipids at multiple membrane-contact sites.
The role of mitochondrial dynamics in oocyte and early embryo development.
Mitochondrial transfer - a novel promising approach for the treatment of metabolic diseases.
Mitochondrial dynamics as a novel treatment strategy for triple-negative breast cancer.
Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status.
Spreading depolarization causes reversible neuronal mitochondria fragmentation and swelling in healthy, normally perfused neocortex.
Prospective Approach to Deciphering the Impact of Intercellular Mitochondrial Transfer from Human Neural Stem Cells and Brain Tumor-Initiating Cells to Neighboring Astrocytes.
Mfn2/Hsc70 Complex Mediates the Formation of Mitochondria-Lipid Droplets Membrane Contact and Regulates Myocardial Lipid Metabolism.
A mammalian-specific Alex3/Gαq protein complex regulates mitochondrial trafficking, dendritic complexity, and neuronal survival.
Drp1-mediated mitochondrial fission promotes pulmonary fibrosis progression through the regulation of lipid metabolic reprogramming by ROS/HIF-1α.
The role of DRP1 mediated mitophagy in HT22 cells apoptosis induced by silica nanoparticles.
Endothelial Mitochondria Transfer to Melanoma Induces M2-Type Macrophage Polarization and Promotes Tumor Growth by the Nrf2/HO-1-Mediated Pathway.
Interplay of Mitochondria and Diabetes: Unveiling Novel Therapeutic Strategies.
Ruxolitinib induces apoptosis and pyroptosis of anaplastic thyroid cancer via the transcriptional inhibition of DRP1-mediated mitochondrial fission.
An aldose reductase inhibitor, WJ-39, ameliorates renal tubular injury in diabetic nephropathy by activating PINK1/Parkin signaling.
Zinc remodels mitochondrial network through SIRT3/Mfn2-dependent mitochondrial transfer in ameliorating spinal cord injury.
Mitochondria-Endoplasmic Reticulum Contact Sites (MERCS): A New Axis in Neuronal Degeneration and Regeneration.
Regulation of proteostasis and innate immunity via mitochondria-nuclear communication.
A break in mitochondrial endosymbiosis as a basis for inflammatory diseases.
Fluvastatin-induced myofibrillar damage is associated with elevated ROS, and impaired fatty acid oxidation, and is preceded by mitochondrial morphological changes.
Transfer of inflammatory mitochondria via extracellular vesicles from M1 macrophages induces ferroptosis of pancreatic beta cells in acute pancreatitis.
The role of mitochondrial uncoupling in the regulation of mitostasis after traumatic brain injury.
AMPK phosphorylation of FNIP1 (S220) controls mitochondrial function and muscle fuel utilization during exercise.
Enhanced translocation of TRIM32 to mitochondria sensitizes dopaminergic neuronal cells to apoptosis during stress conditions in Parkinson's disease.

Curr Mol Med. 2024 Jan 17.

Pharmacological Activation of AMPK Prevents Drp1-mediated Mitochondrial Fission and Alleviates Hepatic Steatosis In vitro.

Jingxia Du, Tingting Wang, Chengyao Xiao, Yibo Dong, Shiyao Zhou, Yujiao Zhu.

   BACKGROUND: The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. Adenosine monophosphate-activated protein kinase (AMPK) activation is beneficial for NAFLD treatment. Recent studies show the excessive fission of mitochondria during NAFLD progression, so targeting mitochondria dynamics may be a possible target for NAFLD. Still, little is known about whether AMPK regulates mitochondrial dynamics in hepar.
OBJECTIVE: This study investigated whether AMPK activation alleviates hepatic steatosis by regulating mitochondrial dynamics mediated by GTPase dynamin-related protein 1 (Drp1).
METHODS: Human hepatocyte line L-02 cells were cultured and subjected to palmitic acid (PA) treatment for 24 h to establish a hepatic steatosis model in vitro, which was pre-treated with different tool drugs. Hepatocyte function, hepatocyte lipid content, mitochondrial reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP) were examined. The expression levels of genes and proteins associated with mitochondrial dynamics were assessed using reverse transcription-quantitative PCR and western blotting.
RESULTS: The results indicated that 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), an AMPK activator, improved hepatocyte function, as demonstrated by decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity (P＜0.05 or P＜0.01). In addition, AICAR decreased total cholesterol (TC) and triglyceride (TG) content and lipid deposition in hepatocytes (P＜0.01); decreased ROS production; improved MMP (P＜0.01); reduced fission-1 (Fis1) and mitochondrial fission factor (Mff) mRNA expression; and downregulated p-Drp1 (Ser 616) protein expression. In contrast, AICAR increased mitochondrial fusion factor mitofusin-1 (Mfn1) and mitofusin-2 (Mfn2) mRNA expression and upregulated p-Drp1 (Ser 637) protein expression. Mdivi-1, a Drp-1 inhibitor, was used to confirm whether mitochondrial dynamics regulated by Drp1-mediated the role of AICAR. Similar to AICAR, Mdivi-1 improved hepatocyte function and MMP significantly, decreased ROS production and lipid deposition, downregulated Fis1 and Mff mRNA expression, downregulated p-Drp1 (Ser 616) protein expression, and enhanced Mfn1 and Mfn2 mRNA and p-Drp1 (Ser 637) protein expression. However, Compound C, an AMPKspecific inhibitor, had less impact on the protective effect of Mdivi-1.
CONCLUSION: The results demonstrated that AMPK activation has a protective effect on hepatic steatosis in vitro, largely dependent on the inhibition of Drp1-mediated mitochondrial fission.

Keywords:  AMPK; Hepatic steatosis; L-02 cell.; MMP; ROS; mitochondrial dynamics

DOI:  https://doi.org/10.2174/0115665240275594231229121030
Semin Cell Dev Biol. 2024 Feb 03. pii: S1084-9521(24)00018-1. [Epub ahead of print]159-160 38-51

Super-resolution microscopies, technological breakthrough to decipher mitochondrial structure and dynamic.

Pauline Teixeira, Rémi Galland, Arnaud Chevrollier.

  Mitochondria are complex organelles with an outer membrane enveloping a second inner membrane that creates a vast matrix space partitioned by pockets or cristae that join the peripheral inner membrane with several thin junctions. Several micrometres long, mitochondria are generally close to 300 nm in diameter, with membrane layers separated by a few tens of nanometres. Ultrastructural data from electron microscopy revealed the structure of these mitochondria, while conventional optical microscopy revealed their extraordinary dynamics through fusion, fission, and migration processes but its limited resolution power restricted the possibility to go further. By overcoming the limits of light diffraction, Super-Resolution Microscopy (SRM) now offers the potential to establish the links between the ultrastructure and remodelling of mitochondrial membranes, leading to major advances in our understanding of mitochondria's structure-function. Here we review the contributions of SRM imaging to our understanding of the relationship between mitochondrial structure and function. What are the hopes for these new imaging approaches which are particularly important for mitochondrial pathologies?

Keywords:  MICOS; Microscopy; Mitochondria; Nucleoids; Super-resolution

DOI:  https://doi.org/10.1016/j.semcdb.2024.01.006
Front Mol Biosci. 2024 ;11 1356500

Navigating the landscape of mitochondrial-ER communication in health and disease.

Conor T Ronayne, Pedro Latorre-Muro.

  Intracellular organelle communication enables the maintenance of tissue homeostasis and health through synchronized adaptive processes triggered by environmental cues. Mitochondrial-Endoplasmic Reticulum (ER) communication sustains cellular fitness by adjusting protein synthesis and degradation, and metabolite and protein trafficking through organelle membranes. Mitochondrial-ER communication is bidirectional and requires that the ER-components of the Integrated Stress Response signal to mitochondria upon activation and, likewise, mitochondria signal to the ER under conditions of metabolite and protein overload to maintain proper functionality and ensure cellular survival. Declines in the mitochondrial-ER communication occur upon ageing and correlate with the onset of a myriad of heterogeneous age-related diseases such as obesity, type 2 diabetes, cancer, or neurodegenerative pathologies. Thus, the exploration of the molecular mechanisms of mitochondrial-ER signaling and regulation will provide insights into the most fundamental cellular adaptive processes with important therapeutical opportunities. In this review, we will discuss the pathways and mechanisms of mitochondrial-ER communication at the mitochondrial-ER interface and their implications in health and disease.

Keywords:  calcium signaling; cellular fitness; endoplasmic reticulum; lipid trafficking; mitochondria; mitochondrial-ER communication; protein homeostasis; unfolded protein response

DOI:  https://doi.org/10.3389/fmolb.2024.1356500
FEBS Lett. 2024 Feb 04.

Remodelling of mitochondrial function by import of specific lipids at multiple membrane-contact sites.

Aksel J Saukko-Paavola, Robin W Klemm.

  Organelles form physical and functional contact between each other to exchange information, metabolic intermediates, and signaling molecules. Tethering factors and contact site complexes bring partnering organelles into close spatial proximity to establish membrane contact sites (MCSs), which specialize in unique functions like lipid transport or Ca2+ signaling. Here, we discuss how MCSs form dynamic platforms that are important for lipid metabolism. We provide a perspective on how import of specific lipids from the ER and other organelles may contribute to remodeling of mitochondria during nutrient starvation. We speculate that mitochondrial adaptation is achieved by connecting several compartments into a highly dynamic organelle network. The lipid droplet appears to be a central hub in coordinating the function of these organelle neighborhoods.

Keywords:  autophagy; endoplasmic reticulum (ER); lipid droplets (LDs); membrane contact sites; metabolic adaptation; mitochondria; mitochondrial shape; organelle-network; starvation

DOI:  https://doi.org/10.1002/1873-3468.14813
Semin Cell Dev Biol. 2024 Feb 06. pii: S1084-9521(24)00019-3. [Epub ahead of print]159-160 52-61

The role of mitochondrial dynamics in oocyte and early embryo development.

Raziye Melike Yildirim, Emre Seli.

  Mitochondrial dysfunction is widely implicated in various human diseases, through mechanisms that go beyond mitochondria's well-established role in energy generation. These dynamic organelles exert vital control over numerous cellular processes, including calcium regulation, phospholipid synthesis, innate immunity, and apoptosis. While mitochondria's importance is acknowledged in all cell types, research has revealed the exceptionally dynamic nature of the mitochondrial network in oocytes and embryos, finely tuned to meet unique needs during gamete and pre-implantation embryo development. Within oocytes, both the quantity and morphology of mitochondria can significantly change during maturation and post-fertilization. These changes are orchestrated by fusion and fission processes (collectively known as mitochondrial dynamics), crucial for energy production, content exchange, and quality control as mitochondria adjust to the shifting energy demands of oocytes and embryos. The roles of proteins that regulate mitochondrial dynamics in reproductive processes have been primarily elucidated through targeted deletion studies in animal models. Notably, impaired mitochondrial dynamics have been linked to female reproductive health, affecting oocyte quality, fertilization, and embryo development. Dysfunctional mitochondria can lead to fertility problems and can have an impact on the success of pregnancy, particularly in older reproductive age women.

Keywords:  Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; MtDNA

DOI:  https://doi.org/10.1016/j.semcdb.2024.01.007
Front Endocrinol (Lausanne). 2023 ;14 1346441

Mitochondrial transfer - a novel promising approach for the treatment of metabolic diseases.

Ruijing Chen, Jun Chen.

  Metabolic disorders remain a major global health concern in the 21st century, with increasing incidence and prevalence. Mitochondria play a critical role in cellular energy production, calcium homeostasis, signal transduction, and apoptosis. Under physiological conditions, mitochondrial transfer plays a crucial role in tissue homeostasis and development. Mitochondrial dysfunction has been implicated in the pathogenesis of metabolic disorders. Numerous studies have demonstrated that mitochondria can be transferred from stem cells to pathologically injured cells, leading to mitochondrial functional restoration. Compared to cell therapy, mitochondrial transplantation has lower immunogenicity, making exogenous transplantation of healthy mitochondria a promising therapeutic approach for treating diseases, particularly metabolic disorders. This review summarizes the association between metabolic disorders and mitochondria, the mechanisms of mitochondrial transfer, and the therapeutic potential of mitochondrial transfer for metabolic disorders. We hope this review provides novel insights into targeted mitochondrial therapy for metabolic disorders.

Keywords:  metabolic diseases; mitochondria; mitochondrial transfer; therapy; transplantation

DOI:  https://doi.org/10.3389/fendo.2023.1346441
Cancer Med. 2024 Jan;13(2): e6987

Mitochondrial dynamics as a novel treatment strategy for triple-negative breast cancer.

Yuechen Wang, Narumi Harada-Shoji, Narufumi Kitamura, Yuto Yamazaki, Akiko Ebata, Masakazu Amari, Mika Watanabe, Minoru Miyashita, Hiroshi Tada, Takaaki Abe, Takashi Suzuki, Kohsuke Gonda, Takanori Ishida.

   INTRODUCTION: Triple-negative breast cancer (TNBC), recognized as the most heterogeneous type of breast cancer (BC), exhibits a worse prognosis than other subtypes. Mitochondria dynamics play a vital role as mediators in tumorigenesis by adjusting to the cell microenvironments. However, the relationship between mitochondrial dynamics and metabophenotype exhibits discrepancies and divergence across various research and BC models. Therefore, this study aims to explore the role of mitochondrial dynamics in TNBC drug resistance and tumorigenesis.
METHODS: The Wst-8 test was conducted to assess doxorubicin sensitivity in HCC38, MDA-MB-231 (TNBC), and MCF-7 (luminal). Confocal microscopy and FACS were used to quantify the mitochondrial membrane potential (ΔφM), mitophagy, and reactive oxygen species (ROS) production. Agilent Seahorse XF Analyzer was utilized to measure metabolic characteristics. Dynamin-related protein-1 (DRP1), Parkin, and p62 immunohistochemistry staining were performed using samples from 107 primary patients with BC before and after neoadjuvant chemotherapy (NAC).
RESULTS: MDA-MB-231, a TNBC cell line with reduced sensitivity to doxorubicin, reduced ΔφM, and enhanced mitophagy to maintain ROS production through oxidative phosphorylation (OXPHOS)-based metabolism. HCC38, a doxorubicin-sensitive cell line, exhibited no alterations in ΔφM or mitophagy. However, it demonstrated an increase in ROS production and glycolysis. Clinicopathological studies revealed that pretreatment (before NAC) expression of DRP1 was significant in TNBC, as was pretreatment expression of Parkin in the hormone receptor-negative group. Furthermore, low p62 levels seem to be a risk factor for recurrence-free survival.
CONCLUSION: Our findings indicated that the interplay between mitophagy, linked to a worse clinical prognosis, and OXPHOS metabolism promoted chemotherapy resistance in TNBC. Mitochondrial fission is prevalent in TNBC. These findings suggest that targeting the unique mitochondrial metabolism and dynamics in TNBC may offer a novel therapeutic strategy for patients with TNBC.

Keywords:  breast cancer; drug resistance; mitochondria; mitophagy

DOI:  https://doi.org/10.1002/cam4.6987
Nat Commun. 2024 Feb 06. 15(1): 1124

Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status.

Aidan Anderson, Nada Alfahad, Dulani Wimalachandra, Kaouthar Bouzinab, Paula Rudzinska, Heather Wood, Isabel Fazey, Heping Xu, Timothy J Lyons, Nicholas M Barnes, Parth Narendran, Janet M Lord, Saaeha Rauz, Ian G Ganley, Tim M Curtis, Graham R Wallace, Jose R Hombrebueno.

The recovery of mitochondrial quality control (MQC) may bring innovative solutions for neuroprotection, while imposing a significant challenge given the need of holistic approaches to restore mitochondrial dynamics (fusion/fission) and turnover (mitophagy and biogenesis). In diabetic retinopathy, this is compounded by our lack of understanding of human retinal neurodegeneration, but also how MQC processes interact during disease progression. Here, we show that mitochondria hyperfusion is characteristic of retinal neurodegeneration in human and murine diabetes, blunting the homeostatic turnover of mitochondria and causing metabolic and neuro-inflammatory stress. By mimicking this mitochondrial remodelling in vitro, we ascertain that N6-furfuryladenosine enhances mitochondrial turnover and bioenergetics by relaxing hyperfusion in a controlled fashion. Oral administration of N6-furfuryladenosine enhances mitochondrial turnover in the diabetic mouse retina (Ins2Akita males), improving clinical correlates and conferring neuroprotection regardless of glycaemic status. Our findings provide translational insights for neuroprotection in the diabetic retina through the holistic recovery of MQC.

DOI: https://doi.org/10.1038/s41467-024-45387-9
bioRxiv. 2024 Jan 22. pii: 2024.01.22.576364. [Epub ahead of print]

Spreading depolarization causes reversible neuronal mitochondria fragmentation and swelling in healthy, normally perfused neocortex.

Jeremy Sword, Ioulia V Fomitcheva, Sergei A Kirov.

Mitochondrial function is tightly linked to their morphology, and fragmentation of dendritic mitochondria during noxious conditions suggests loss of function. In the normoxic cortex, spreading depolarization (SD) is a phenomenon underlying migraine aura. It is unknown whether mitochondria structure is affected by normoxic SD. In vivo two-photon imaging followed by quantitative serial section electron microscopy (ssEM) was used to monitor dendritic mitochondria in the normoxic cortex of urethane-anesthetized mature male and female mice during and after SD initiated by focal KCl microinjection. Structural dynamics of dendrites and their mitochondria were visualized by transfecting excitatory, glutamatergic neurons of the somatosensory cortex with bicistronic AAV, which induced tdTomoto labeling in neuronal cytoplasm and mitochondria labeling with roGFP. Normoxic SD triggered a rapid fragmentation of dendritic mitochondria alongside dendritic beading, both reversible; however, mitochondria took significantly longer to recover. Several rounds of SD resulted in transient mitochondrial fragmentation and dendritic beading without accumulating injury, as both recovered. SsEM corroborated normoxic SD-elicited dendritic and mitochondrial swelling and transformation of the filamentous mitochondrial network into shorter, swollen tubular and globular structures. Our results revealed normoxic SD-induced disruption of the dendritic mitochondrial structure that might impact mitochondrial bioenergetics during migraine with aura.

DOI: https://doi.org/10.1101/2024.01.22.576364
Cells. 2024 Jan 23. pii: 204. [Epub ahead of print]13(3):

Prospective Approach to Deciphering the Impact of Intercellular Mitochondrial Transfer from Human Neural Stem Cells and Brain Tumor-Initiating Cells to Neighboring Astrocytes.

Jerusha Boyineni, Jason Michael Wood, Aditya Ravindra, Ethan Boley, Sarah E Donohue, Marcelo Bento Soares, Sergey Malchenko.

  The communication between neural stem cells (NSCs) and surrounding astrocytes is essential for the homeostasis of the NSC niche. Intercellular mitochondrial transfer, a unique communication system that utilizes the formation of tunneling nanotubes for targeted mitochondrial transfer between donor and recipient cells, has recently been identified in a wide range of cell types. Intercellular mitochondrial transfer has also been observed between different types of cancer stem cells (CSCs) and their neighboring cells, including brain CSCs and astrocytes. CSC mitochondrial transfer significantly enhances overall tumor progression by reprogramming neighboring cells. Despite the urgent need to investigate this newly identified phenomenon, mitochondrial transfer in the central nervous system remains largely uncharacterized. In this study, we found evidence of intercellular mitochondrial transfer from human NSCs and from brain CSCs, also known as brain tumor-initiating cells (BTICs), to astrocytes in co-culture experiments. Both NSC and BTIC mitochondria triggered similar transcriptome changes upon transplantation into the recipient astrocytes. In contrast to NSCs, the transplanted mitochondria from BTICs had a significant proliferative effect on the recipient astrocytes. This study forms the basis for mechanistically deciphering the impact of intercellular mitochondrial transfer on recipient astrocytes, which will potentially provide us with new insights into the mechanisms of mitochondrial retrograde signaling.

Keywords:  astrocytes; cancer stem cells; intercellular mitochondrial transfer; neural stem cells

DOI:  https://doi.org/10.3390/cells13030204
Adv Sci (Weinh). 2024 Feb 04. e2307749

Mfn2/Hsc70 Complex Mediates the Formation of Mitochondria-Lipid Droplets Membrane Contact and Regulates Myocardial Lipid Metabolism.

Lang Hu, Daishi Tang, Bingchao Qi, Dong Guo, Ying Wang, Jing Geng, Xiaoliang Zhang, Liqiang Song, Pan Chang, Wensheng Chen, Feng Fu, Yan Li.

  The heart primarily derives its energy through lipid oxidation. In cardiomyocytes, lipids are stored in lipid droplets (LDs) and are utilized in mitochondria, although the structural and functional connections between these two organelles remain largely unknown. In this study, visible evidence have presented indicating that a complex is formed at the mitochondria-LD membrane contact (MLC) site, involving mitochondrion-localized Mfn2 and LD-localized Hsc70. This complex serves to tether mitochondria to LDs, facilitating the transfer of fatty acids (FAs) from LDs to mitochondria for β-oxidation. Reduction of Mfn2 induced by lipid overload inhibits MLC, hinders FA transfer, and results in lipid accumulation. Restoring Mfn2 reinstates MLC, alleviating myocardial lipotoxicity under lipid overload conditions both in-vivo and in-vitro. Additionally, prolonged lipid overload induces Mfn2 degradation through the ubiquitin-proteasome pathway, following Mfn2 acetylation at the K243 site. This leads to the transition from adaptive lipid utilization to maladaptive lipotoxicity. The experimental findings are supported by clinical data from patients with obesity and age-matched non-obese individuals. These translational results make a significant contribution to the molecular understanding of MLC in the heart, and offer new insights into its role in myocardial lipotoxicity.

Keywords:  Hsc70; Mfn2; lipid overload; mitochondrion-lipid droplets membrane contacts; myocardial lipotoxicity

DOI:  https://doi.org/10.1002/advs.202307749
Sci Signal. 2024 Feb 06. 17(822): eabq1007

A mammalian-specific Alex3/Gαq protein complex regulates mitochondrial trafficking, dendritic complexity, and neuronal survival.

Ismael Izquierdo-Villalba, Serena Mirra, Yasmina Manso, Antoni Parcerisas, Javier Rubio, Jaume Del Valle, Francisco J Gil-Bea, Fausto Ulloa, Marina Herrero-Lorenzo, Ester Verdaguer, Cristiane Benincá, Rubén D Castro-Torres, Elena Rebollo, Gemma Marfany, Carme Auladell, Xavier Navarro, José A Enríquez, Adolfo López de Munain, Eduardo Soriano, Anna M Aragay.

Mitochondrial dynamics and trafficking are essential to provide the energy required for neurotransmission and neural activity. We investigated how G protein-coupled receptors (GPCRs) and G proteins control mitochondrial dynamics and trafficking. The activation of Gαq inhibited mitochondrial trafficking in neurons through a mechanism that was independent of the canonical downstream PLCβ pathway. Mitoproteome analysis revealed that Gαq interacted with the Eutherian-specific mitochondrial protein armadillo repeat-containing X-linked protein 3 (Alex3) and the Miro1/Trak2 complex, which acts as an adaptor for motor proteins involved in mitochondrial trafficking along dendrites and axons. By generating a CNS-specific Alex3 knockout mouse line, we demonstrated that Alex3 was required for the effects of Gαq on mitochondrial trafficking and dendritic growth in neurons. Alex3-deficient mice had altered amounts of ER stress response proteins, increased neuronal death, motor neuron loss, and severe motor deficits. These data revealed a mammalian-specific Alex3/Gαq mitochondrial complex, which enables control of mitochondrial trafficking and neuronal death by GPCRs.

DOI: https://doi.org/10.1126/scisignal.abq1007
Cell Signal. 2024 Feb 02. pii: S0898-6568(24)00043-3. [Epub ahead of print]117 111075

Drp1-mediated mitochondrial fission promotes pulmonary fibrosis progression through the regulation of lipid metabolic reprogramming by ROS/HIF-1α.

Zhongkai Tong, Xuekui Du, Ying Zhou, Fangxue Jing, JiangPo Ma, Yingying Feng, Saiyun Lou, Qiong Wang, Zhaoxing Dong.

   OBJECTIVE: To confirm the mechanism of dynamic-related protein 1 (Drp1)-mediated mitochondrial fission through ROS/HIF-1α-mediated regulation of lipid metabolic reprogramming in the progression of pulmonary fibrosis (PF).
METHODS: A mouse model of PF was established by intratracheal instillation of bleomycin (BLM) (2.5 mg/kg). A PF cell model was constructed by stimulating MRC-5 cells with TGF-β (10 ng/mL). Pathological changes in the lung tissue and related protein levels were observed via tissue staining. The indicators related to lipid oxidation were detected by a kit, and lipid production was confirmed through oil red O staining. Inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). RT-qPCR, Western blotting and immunofluorescence staining were used to detect the expression of genes and proteins related to the disease. We used CCK-8 and EdU staining to confirm cell proliferation, flow cytometry was used to confirm apoptosis and ROS levels, α-SMA expression was detected by immunofluorescence staining, and mitochondria were observed by MitoTracker staining.
RESULTS: The BLM induced lung tissue structure and alveolar wall thickening in mice. Mitochondrial fission was observed in MRC-5 cells induced by TGF-β, which led to increased cell proliferation; decreased apoptosis; increased expression of collagen, α-SMA and Drp1; and increased lipid oxidation and inflammation. Treatment with the Drp1 inhibitor mdivi-1 or transfection with si-Drp1 attenuated the induction of BLM and TGF-β. For lipid metabolism, lipid droplets were formed in BLM-induced lung tissue and in TGF-β-induced cells, fatty acid oxidation genes and lipogenesis-related genes were upregulated, ROS levels in cells were increased, and the expression of HIF-1α was upregulated. Mdivi-1 treatment reversed TGF-β induction, while H2O2 treatment or OE-HIF-1α transfection reversed the effect of mdivi-1.
CONCLUSION: In PF, inhibition of Drp1 can prevent mitochondrial fission in fibroblasts and regulate lipid metabolism reprogramming through ROS/HIF-1α; thus, fibroblast activation was inhibited, alleviating the progression of PF.

Keywords:  Drp1; HIF-1α; Lipid metabolism; Mitochondrial fission; Pulmonary fibrosis; ROS

DOI:  https://doi.org/10.1016/j.cellsig.2024.111075
Ecotoxicol Environ Saf. 2024 Feb 05. pii: S0147-6513(24)00125-8. [Epub ahead of print]272 116050

The role of DRP1 mediated mitophagy in HT22 cells apoptosis induced by silica nanoparticles.

Tiantian Tian, Huan Pang, Xinyue Li, Kai Ma, Tianxiang Liu, Jiali Li, Zhixuan Luo, Meng Li, Qiaohong Hou, Huifang Hao, Jianfei Dong, Haiying Du, Xiaomei Liu, Zhiwei Sun, Chao Zhao, Xiuling Song, Minghua Jin.

  Silica nanoparticles (SiNPs) are widely used in the biomedical field and can enter the central nervous system through the blood-brain barrier, causing damage to hippocampal neurons. However, the specific mechanism remains unclear. In this experiment, HT22 cells were selected as the experimental model in vitro, and the survival rate of cells under the action of SiNPs was detected by MTT method, reactive oxygen species (ROS), lactate dehydrogenase (LDH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and adenosine triphosphate (ATP) were tested by the kit, the ultrastructure of the cells was observed by transmission electron microscope, membrane potential (MMP), calcium ion (Ca2+) and apoptosis rate were measured by flow cytometry, and the expressions of mitochondrial functional protein, mitochondrial dynein, mitochondrial autophagy protein as well as apoptosis related protein were detected by Western blot. The results showed that cell survival rate, SOD, CAT, GSH-Px, ATP and MMP gradually decreased with the increase of SiNPs concentration, while intracellular ROS, Ca2+, LDH and apoptosis rate increased with the increase of SiNPs concentration. In total cellular proteins,the expressions of mitochondrial functional proteins VDAC and UCP2 gradually increased, the expression of mitochondrial dynamic related protein DRP1 increased while the expressions of OPA1 and Mfn2 decreased. The expressions of mitophagy related proteins PINK1, Parkin and LC3Ⅱ/LC3Ⅰ increased and P62 gradually decreased, as well as the expressions of apoptosis related proteins Apaf-1, Cleaved-Caspase-3, Caspase-3, Caspase-9, Bax and Cyt-C. In mitochondrial proteins, the expressions of mitochondrial dynamic related proteins DRP1 and p-DRP1 were increased, while the expressions of OPA1 and Mfn2 were decreased. Expressions of mitochondrial autophagy associated proteins PINK1, Parkin, LC3II/LC3I increased, P62 decreased gradually, as well as the expressions of apoptosis related proteins Cleaved-Caspase-3, Caspase-3, and Caspase-9 increased, and Cyt-C expressions decreased. To further demonstrate the role of ROS and DRP1 in HT22 cell apoptosis induced by SiNPs, we selected the ROS inhibitor N-Acetylcysteine (NAC) and Dynamin-related protein 1 (DRP1) inhibitor Mdivi-1. The experimental results indicated that the above effects were remarkably improved after the use of inhibitors, further confirming that SiNPs induce the production of ROS in cells, activate DRP1, cause excessive mitochondrial division, induce mitophagy, destroy mitochondrial function and eventually lead to apoptosis.

Keywords:  Dynamin-related protein 1 (DRP1); HT22; Mitochondria; Mitophagy; Oxidative damage; Silica nanoparticles (SiNPs)

DOI:  https://doi.org/10.1016/j.ecoenv.2024.116050
Int J Mol Sci. 2024 Feb 03. pii: 1857. [Epub ahead of print]25(3):

Endothelial Mitochondria Transfer to Melanoma Induces M2-Type Macrophage Polarization and Promotes Tumor Growth by the Nrf2/HO-1-Mediated Pathway.

Fu-Chen Kuo, Hsin-Yi Tsai, Bi-Ling Cheng, Kuen-Jang Tsai, Ping-Chen Chen, Yaw-Bin Huang, Chung-Jung Liu, Deng-Chyang Wu, Meng-Chieh Wu, Bin Huang, Ming-Wei Lin.

  Gynecologic tract melanoma is a malignant tumor with poor prognosis. Because of the low survival rate and the lack of a standard treatment protocol related to this condition, the investigation of the mechanisms underlying melanoma progression is crucial to achieve advancements in the relevant gynecological surgery and treatment. Mitochondrial transfer between adjacent cells in the tumor microenvironment regulates tumor progression. This study investigated the effects of endothelial mitochondria on the growth of melanoma cells and the activation of specific signal transduction pathways following mitochondrial transplantation. Mitochondria were isolated from endothelial cells (ECs) and transplanted into B16F10 melanoma cells, resulting in the upregulation of proteins associated with tumor growth. Furthermore, enhanced antioxidation and mitochondrial homeostasis mediated by the Sirt1-PGC-1α-Nrf2-HO-1 pathway were observed, along with the inhibition of apoptotic protein caspase-3. Finally, the transplantation of endothelial mitochondria into B16F10 cells promoted tumor growth and increased M2-type macrophages through Nrf2/HO-1-mediated pathways in a xenograft animal model. In summary, the introduction of exogenous mitochondria from ECs into melanoma cells promoted tumor growth, indicating the role of mitochondrial transfer by stromal cells in modulating a tumor's phenotype. These results provide valuable insights into the role of mitochondrial transfer and provide potential targets for gynecological melanoma treatment.

Keywords:  M2-type macrophage; Nrf2; endothelial cells; melanoma; mitochondrial transplantation; tumor growth; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms25031857
Mitochondrion. 2024 Feb 06. pii: S1567-7249(24)00008-4. [Epub ahead of print] 101850

Interplay of Mitochondria and Diabetes: Unveiling Novel Therapeutic Strategies.

Kristina Xiao Liang.

The interplay between mitochondrial function and diabetes has gained significant attention due to its crucial role in the pathogenesis and progression of the disease. Mitochondria, known as the cellular powerhouses, are essential for glucose metabolism. Dysfunction of these organelles has been implicated in the development of insulin resistance and beta-cell failure, both prominent features of diabetes. This comprehensive review explores the intricate mechanisms involved, including the generation of reactive oxygen species and the impact of mitochondrial DNA mutations. Moreover, the review delves into emerging therapeutic strategies that specifically target mitochondria, such as mitochondria-targeted antioxidants, agents promoting mitochondrial biogenesis, and compounds modulating mitochondrial dynamics. The potential of these novel approaches is critically evaluated, taking into account their benefits and limitations, to provide a well-rounded perspective. Ultimately, this review emphasizes the importance of advancing our understanding of mitochondrial biology to revolutionize the treatment of diabetes.

DOI: https://doi.org/10.1016/j.mito.2024.101850
Cell Death Dis. 2024 Feb 09. 15(2): 125

Ruxolitinib induces apoptosis and pyroptosis of anaplastic thyroid cancer via the transcriptional inhibition of DRP1-mediated mitochondrial fission.

Ya-Wen Guo, Lei Zhu, Yan-Ting Duan, Yi-Qun Hu, Le-Bao Li, Wei-Jiao Fan, Fa-Huan Song, Ye-Feng Cai, Yun-Ye Liu, Guo-Wan Zheng, Ming-Hua Ge.

Anaplastic thyroid carcinoma (ATC) has a 100% disease-specific mortality rate. The JAK1/2-STAT3 pathway presents a promising target for treating hematologic and solid tumors. However, it is unknown whether the JAK1/2-STAT3 pathway is activated in ATC, and the anti-cancer effects and the mechanism of action of its inhibitor, ruxolitinib (Ruxo, a clinical JAK1/2 inhibitor), remain elusive. Our data indicated that the JAK1/2-STAT3 signaling pathway is significantly upregulated in ATC tumor tissues than in normal thyroid and papillary thyroid cancer tissues. Apoptosis and GSDME-pyroptosis were observed in ATC cells following the in vitro and in vivo administration of Ruxo. Mechanistically, Ruxo suppresses the phosphorylation of STAT3, resulting in the repression of DRP1 transactivation and causing mitochondrial fission deficiency. This deficiency is essential for activating caspase 9/3-dependent apoptosis and GSDME-mediated pyroptosis within ATC cells. In conclusion, our findings indicate DRP1 is directly regulated and transactivated by STAT3; this exhibits a novel and crucial aspect of JAK1/2-STAT3 on the regulation of mitochondrial dynamics. In ATC, the transcriptional inhibition of DRP1 by Ruxo hampered mitochondrial division and triggered apoptosis and GSDME-pyroptosis through caspase 9/3-dependent mechanisms. These results provide compelling evidence for the potential therapeutic effectiveness of Ruxo in treating ATC.

DOI: https://doi.org/10.1038/s41419-024-06511-1
Eur J Pharmacol. 2024 Feb 07. pii: S0014-2999(24)00064-5. [Epub ahead of print] 176376

An aldose reductase inhibitor, WJ-39, ameliorates renal tubular injury in diabetic nephropathy by activating PINK1/Parkin signaling.

Luxi Yang, Liangting Xu, Xin Hao, Zhixiao Song, Xian Zhang, Peng Liu, Shaojie Wang, Zhonggui He, Libo Zou.

  Renal tubular injury is a critical factor during the early stages of diabetic nephropathy (DN). Proximal tubular epithelial cells, which contain abundant mitochondria essential for intracellular homeostasis, are susceptible to disruptions in the intracellular environment, making them especially vulnerable to diabetic state disorders, which may be attributed to their elevated energy requirements and reliance on aerobic metabolism. It is widely thought that overactivation of the polyol pathway is implicated in DN pathogenesis, and inhibition of aldose reductase (AR), the rate-limiting enzyme in this pathway, represents a promising therapeutic avenue. WJ-39, a novel aldose reductase inhibitor, was investigated in this study for its protective effects on renal tubules in DN and the underlying mechanisms. Our findings revealed that WJ-39 significantly ameliorated the renal tubular morphology in high-fat diet (HFD)/streptozotocin (STZ)-induced DN rats, concurrently inhibiting fibrosis. Notably, WJ-39 safeguarded the structure and function of renal tubular mitochondria by enhancing mitochondrial dynamics. This involved the regulation of mitochondrial fission and fusion proteins and the promotion of PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy. Furthermore, WJ-39 demonstrated the inhibition of endogenous apoptosis by mitigating the production of mitochondrial reactive oxygen species (ROS). The protective effects of WJ-39 on mitochondria and apoptosis were countered in high glucose-treated HK-2 cells upon transfection with PINK1 siRNA. Overall, our findings suggest that WJ-39 protects the structural and functional integrity of renal tubules in DN, which may be attributed to its capacity to inhibit aldose reductase activity, activate the PINK1/Parkin signaling pathway, promote mitophagy, and alleviate apoptosis.

Keywords:  Aldose reductase; Apoptosis; Diabetic nephropathy; Mitophagy; Renal tubule

DOI:  https://doi.org/10.1016/j.ejphar.2024.176376
Eur J Pharmacol. 2024 Feb 03. pii: S0014-2999(24)00056-6. [Epub ahead of print] 176368

Zinc remodels mitochondrial network through SIRT3/Mfn2-dependent mitochondrial transfer in ameliorating spinal cord injury.

Hui Guo, Li-Qing Chen, Zhi-Ru Zou, Shuai Cheng, Yu Hu, Liang Mao, He Tian, Xi-Fan Mei.

  Spinal cord injury (SCI) is a traumatic neuropathic condition that results in motor, sensory and autonomic dysfunction. Mitochondrial dysfunction caused by primary trauma is one of the critical pathogenic mechanisms. Moderate levels of zinc have antioxidant effects, promote neurogenesis and immune responses. Zinc normalises mitochondrial morphology in neurons after SCI. However, how zinc protects mitochondria within neurons is unknown. In the study, we used transwell culture, Western blot, Quantitative Real-time Polymerase Chain Reaction (QRT-PCR), ATP content detection, reactive oxygen species (ROS) activity assay, flow cytometry and immunostaining to investigate the relationship between zinc-treated microglia and injured neurons through animal and cell experiments. We found that zinc promotes mitochondrial transfer from microglia to neurons after SCI through Sirtuin 3 (SIRT3) regulation of Mitofusin 2 protein (Mfn2). It can rescue mitochondria in damaged neurons and inhibit oxidative stress, increase ATP levels and promote neuronal survival. Therefore, it can improve the recovery of motor function in SCI mice. In conclusion, our work reveals a potential mechanism to describe the communication between microglia and neurons after SCI, which may provide a new idea for future therapeutic approaches to SCI.

Keywords:  Mfn2; Mitochondrial network; Mitochondrial transfer; SIRT3; Zinc

DOI:  https://doi.org/10.1016/j.ejphar.2024.176368
Mol Neurobiol. 2024 Feb 06.

Mitochondria-Endoplasmic Reticulum Contact Sites (MERCS): A New Axis in Neuronal Degeneration and Regeneration.

Vijaya Harini Sathyamurthy, Yoghalakshmi Nagarajan, Venkatachalam Deepa Parvathi.

  Mitochondria-Endoplasmic Reticulum Contact Sites (MERCS) are dynamic structures whose physiological interaction is vital to direct life and death of the cell. A bevy of tethering proteins, mitofusin-1/2 (Mfn-1/2), glucose-regulated protein-75 (Grp-75), voltage-dependent anion channel-1 (VDAC1), and dynamic-related protein-1 (Drp1), plays an integral role in establishing and regulating this intricate intracellular communication. Dysregulation of this interplay leads to various neurodegenerative disorders, like Alzheimer's disease (AD), Parkinson's disease (PD), stroke, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Although there is an absence of a well-defined molecular background that dictates the pathway of MERCS, adequate exploration has resulted in preliminary data that suggests its cardinal role in neuroregeneration. The juxtaposition of mitochondria and ER has a critical function in cell senescence, thus regulating regeneration. Axonal regeneration and brain tissue regeneration, using reactive astrocytes, are studied most extensively. Overexpression of Grp-75 promoted axonal regeneration post a nerve injury. Attempts have been made to exploit MERCS as potential therapeutic drug targets for enhancing neuroregeneration and impeding neurodegeneration. Novel strategies have been developed to aid the delivery of mitochondria into the neuronal cell body, which in turn establishes a network with the presiding ER resulting in contact site formation. The fascinating aspect of this mechanism is that despite the lack of inherent regenerative capacity in neurons, it can be induced by modifying MERCS.

Keywords:  Axonal regeneration; Mitochondria-Endoplasmic Reticulum Contact Sites (MERCS); Neurodegenerative diseases; Targeted therapy

DOI:  https://doi.org/10.1007/s12035-024-03971-6
J Cell Biol. 2024 Mar 04. pii: e202310005. [Epub ahead of print]223(3):

Regulation of proteostasis and innate immunity via mitochondria-nuclear communication.

Sookyung Kim, Theresa R Ramalho, Cole M Haynes.

Mitochondria are perhaps best known as the "powerhouse of the cell" for their role in ATP production required for numerous cellular activities. Mitochondria have emerged as an important signaling organelle. Here, we first focus on signaling pathways mediated by mitochondria-nuclear communication that promote protein homeostasis (proteostasis). We examine the mitochondrial unfolded protein response (UPRmt) in C. elegans, which is regulated by a transcription factor harboring both a mitochondrial- and nuclear-targeting sequence, the integrated stress response in mammals, as well as the regulation of chromatin by mitochondrial metabolites. In the second section, we explore the role of mitochondria-to-nuclear communication in the regulation of innate immunity and inflammation. Perhaps related to their prokaryotic origin, mitochondria harbor molecules also found in viruses and bacteria. If these molecules accumulate in the cytosol, they elicit the same innate immune responses as viral or bacterial infection.

DOI: https://doi.org/10.1083/jcb.202310005
Nature. 2024 Feb;626(7998): 271-279

A break in mitochondrial endosymbiosis as a basis for inflammatory diseases.

Michael P Murphy, Luke A J O'Neill.

Mitochondria retain bacterial traits due to their endosymbiotic origin, but host cells do not recognize them as foreign because the organelles are sequestered. However, the regulated release of mitochondrial factors into the cytosol can trigger cell death, innate immunity and inflammation. This selective breakdown in the 2-billion-year-old endosymbiotic relationship enables mitochondria to act as intracellular signalling hubs. Mitochondrial signals include proteins, nucleic acids, phospholipids, metabolites and reactive oxygen species, which have many modes of release from mitochondria, and of decoding in the cytosol and nucleus. Because these mitochondrial signals probably contribute to the homeostatic role of inflammation, dysregulation of these processes may lead to autoimmune and inflammatory diseases. A potential reason for the increased incidence of these diseases may be changes in mitochondrial function and signalling in response to such recent phenomena as obesity, dietary changes and other environmental factors. Focusing on the mixed heritage of mitochondria therefore leads to predictions for future insights, research paths and therapeutic opportunities. Thus, whereas mitochondria can be considered 'the enemy within' the cell, evolution has used this strained relationship in intriguing ways, with increasing evidence pointing to the recent failure of endosymbiosis being critical for the pathogenesis of inflammatory diseases.

DOI: https://doi.org/10.1038/s41586-023-06866-z
Sci Rep. 2024 Feb 09. 14(1): 3338

Fluvastatin-induced myofibrillar damage is associated with elevated ROS, and impaired fatty acid oxidation, and is preceded by mitochondrial morphological changes.

Mohamed H Al-Sabri, Nourhane Ammar, Stanislava Korzh, Ahmed M Alsehli, Kimia Hosseini, Robert Fredriksson, Jessica Mwinyi, Michael J Williams, Hadi Boukhatmi, Helgi B Schiöth.

Previously, we showed that fluvastatin treatment induces myofibrillar damage and mitochondrial phenotypes in the skeletal muscles of Drosophila. However, the sequential occurrence of mitochondrial phenotypes and myofibril damage remains elusive. To address this, we treated flies with fluvastatin for two and five days and examined their thorax flight muscles using confocal microscopy. In the two-day fluvastatin group, compared to the control, thorax flight muscles exhibited mitochondrial morphological changes, including fragmentation, rounding up and reduced content, while myofibrils remained organized in parallel. In the five-day fluvastatin treatment, not only did mitochondrial morphological changes become more pronounced, but myofibrils became severely disorganized with significantly increased thickness and spacing, along with myofilament abnormalities, suggesting myofibril damage. These findings suggest that fluvastatin-induced mitochondrial changes precede myofibril damage. Moreover, in the five-day fluvastatin group, the mitochondria demonstrated elevated H2O2 and impaired fatty acid oxidation compared to the control group, indicating potential mitochondrial dysfunction. Surprisingly, knocking down Hmgcr (Drosophila homolog of HMGCR) showed normal mitochondrial respiration in all parameters compared to controls or five-day fluvastatin treatment, which suggests that fluvastatin-induced mitochondrial dysfunction might be independent of Hmgcr inhibition. These results provide insights into the sequential occurrence of mitochondria and myofibril damage in statin-induced myopathy for future studies.

DOI: https://doi.org/10.1038/s41598-024-53446-w
J Extracell Vesicles. 2024 Feb;13(2): e12410

Transfer of inflammatory mitochondria via extracellular vesicles from M1 macrophages induces ferroptosis of pancreatic beta cells in acute pancreatitis.

Yuhua Gao, Ningning Mi, Wenxiang Wu, Yuxuan Zhao, Fangzhou Fan, Wangwei Liao, Yongliang Ming, Weijun Guan, Chunyu Bai.

  Extracellular vesicles (EVs) exert a significant influence not only on the pathogenesis of diseases but also on their therapeutic interventions, contingent upon the variances observed in their originating cells. Mitochondria can be transported between cells via EVs to promote pathological changes. In this study, we found that EVs derived from M1 macrophages (M1-EVs), which encapsulate inflammatory mitochondria, can penetrate pancreatic beta cells. Inflammatory mitochondria fuse with the mitochondria of pancreatic beta cells, resulting in lipid peroxidation and mitochondrial disruption. Furthermore, fragments of mitochondrial DNA (mtDNA) are released into the cytosol, activating the STING pathway and ultimately inducing apoptosis. The potential of adipose-derived stem cell (ADSC)-released EVs in suppressing M1 macrophage reactions shows promise. Subsequently, ADSC-EVs were utilized and modified with an F4/80 antibody to specifically target macrophages, aiming to treat ferroptosis of pancreatic beta cells in vivo. In summary, our data further demonstrate that EVs secreted from M1 phenotype macrophages play major roles in beta cell ferroptosis, and the modified ADSC-EVs exhibit considerable potential for development as a vehicle for targeted delivery to macrophages.

Keywords:  M1 macrophages; extracellular vesicles; ferroptosis; mitochondria; pancreatic beta cells

DOI:  https://doi.org/10.1002/jev2.12410
Neurochem Int. 2024 Feb 02. pii: S0197-0186(24)00007-X. [Epub ahead of print] 105680

The role of mitochondrial uncoupling in the regulation of mitostasis after traumatic brain injury.

W Brad Hubbard, Gopal V Velmurugan, Patrick G Sullivan.

  Mitostasis, the maintenance of healthy mitochondria, plays a critical role in brain health. The brain's high energy demands and reliance on mitochondria for energy production make mitostasis vital for neuronal function. Traumatic brain injury (TBI) disrupts mitochondrial homeostasis, leading to secondary cellular damage, neuronal degeneration, and cognitive deficits. Mild mitochondrial uncoupling, which dissociates ATP production from oxygen consumption, offers a promising avenue for TBI treatment. Accumulating evidence, from endogenous and exogenous mitochondrial uncoupling, suggests that mitostasis is closely regulating by mitochondrial uncoupling and cellular injury environments may be more sensitive to uncoupling. Mitochondrial uncoupling can mitigate calcium overload, reduce oxidative stress, and induce mitochondrial proteostasis and mitophagy, a process that eliminates damaged mitochondria. The interplay between mitochondrial uncoupling and mitostasis is ripe for further investigation in the context of TBI. These multi-faceted mechanisms of action for mitochondrial uncoupling hold promise for TBI therapy, with the potential to restore mitochondrial health, improve neurological outcomes, and prevent long-term TBI-related pathology.

Keywords:  Calcium; Dinitrophenol; Mitochondria; Mitophagy; Oxidative stress

DOI:  https://doi.org/10.1016/j.neuint.2024.105680
Sci Adv. 2024 Feb 09. 10(6): eadj2752

AMPK phosphorylation of FNIP1 (S220) controls mitochondrial function and muscle fuel utilization during exercise.

Liwei Xiao, Yujing Yin, Zongchao Sun, Jing Liu, Yuhuan Jia, Likun Yang, Yan Mao, Shujun Peng, Zhifu Xie, Lei Fang, Jingya Li, Xiaoduo Xie, Zhenji Gan.

Exercise-induced activation of adenosine monophosphate-activated protein kinase (AMPK) and substrate phosphorylation modulate the metabolic capacity of mitochondria in skeletal muscle. However, the key effector(s) of AMPK and the regulatory mechanisms remain unclear. Here, we showed that AMPK phosphorylation of the folliculin interacting protein 1 (FNIP1) serine-220 (S220) controls mitochondrial function and muscle fuel utilization during exercise. Loss of FNIP1 in skeletal muscle resulted in increased mitochondrial content and augmented metabolic capacity, leading to enhanced exercise endurance in mice. Using skeletal muscle-specific nonphosphorylatable FNIP1 (S220A) and phosphomimic (S220D) transgenic mouse models as well as biochemical analysis in primary skeletal muscle cells, we demonstrated that exercise-induced FNIP1 (S220) phosphorylation by AMPK in muscle regulates mitochondrial electron transfer chain complex assembly, fuel utilization, and exercise performance without affecting mechanistic target of rapamycin complex 1-transcription factor EB signaling. Therefore, FNIP1 is a multifunctional AMPK effector for mitochondrial adaptation to exercise, implicating a mechanism for exercise tolerance in health and disease.

DOI: https://doi.org/10.1126/sciadv.adj2752
FEBS J. 2024 Feb 05.

Enhanced translocation of TRIM32 to mitochondria sensitizes dopaminergic neuronal cells to apoptosis during stress conditions in Parkinson's disease.

Shanikumar Goyani, Anjali Shinde, Shatakshi Shukla, M V Saranga, Fatema Currim, Minal Mane, Jyoti Singh, Milton Roy, Dhruv Gohel, Nisha Chandak, Hitesh Vasiyani, Rajesh Singh.

  Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by progressive loss of dopamine-producing neurons from the substantia nigra region of the brain. Mitochondrial dysfunction is one of the major causes of oxidative stress and neuronal cell death in PD. E3 ubiquitin ligases such as Parkin (PRKN) modulate mitochondrial quality control in PD; however, the role of other E3 ligases associated with mitochondria in the regulation of neuronal cell death in PD has not been explored. The current study investigated the role of TRIM32, RING E3 ligase, in sensitization to oxidative stress-induced neuronal apoptosis. The expression of TRIM32 sensitizes SH-SY5Y dopaminergic cells to rotenone and 6-OHDA-induced neuronal death, whereas the knockdown increased cell viability under PD stress conditions. The turnover of TRIM32 is enhanced under PD stress conditions and is mediated by autophagy. TRIM32 translocation to mitochondria is enhanced under PD stress conditions and localizes on the outer mitochondrial membrane. TRIM32 decreases complex-I assembly and activity as well as mitochondrial reactive oxygen species (ROS) and ATP levels under PD stress. Deletion of the RING domain of TRIM32 enhanced complex I activity and rescued ROS levels and neuronal viability under PD stress conditions. TRIM32 decreases the level of XIAP, and co-expression of XIAP with TRIM32 rescued the PD stress-induced cell death and mitochondrial ROS level. In conclusion, turnover of TRIM32 increases during stress conditions and translocation to mitochondria is enhanced, regulating mitochondrial functions and neuronal apoptosis by modulating the level of XIAP in PD.

Keywords:  Parkinson's disease; TRIM32; XIAP; cell death; mitochondria

DOI:  https://doi.org/10.1111/febs.17065