bims-midtic 2023-12-17 papers

bims-midtic

Biomed News

on Mitochondrial dynamics and trafficking in cells

Issue of 2023–12–17
twenty-six papers selected by
Omkar Joshi, Turku Bioscience

Multiomics Reveals Induction of Neuroblastoma SK-N-BE(2)C Cell Death by Mitochondrial Division Inhibitor 1 through Multiple Effects.
CMT2A-linked MFN2 mutation, T206I promotes mitochondrial hyperfusion and predisposes cells towards mitophagy.
Molecular Mechanisms Underlying TNFα Induced Mitochondrial Fragmentation in Human Airway Smooth Muscle Cells.
Cadmium-induced global DNA hypermethylation promoting mitochondrial dynamics dysregulation in hippocampal neurons.
GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis.
Caveolin-1 promotes mitochondrial health and limits mitochondrial ROS through ROCK/AMPK regulation of basal mitophagic flux.
The interplay between sex, time of day, fasting status, and their impact on cardiac mitochondrial structure, function, and dynamics.
NOX4 alleviates breast cancer cell aggressiveness by co-ordinating mitochondrial turnover through PGC1α/Drp1 axis.
Mitochondrial Dyshomeostasis as an Early Hallmark and a Therapeutic Target in Amyotrophic Lateral Sclerosis.
Mitochondrial morphology in the mouse adrenal cortex: Influence of chronic psychosocial stress.
DRP1: At the Crossroads of Dysregulated Mitochondrial Dynamics and Altered Cell Signaling in Cancer Cells.
Tom70-regulated mitochondrial biogenesis via TFAM improves hypoxia-induced dysfunction of pulmonary vascular endothelial cells and alleviates hypoxic pulmonary hypertension.
Parkin-mediated mitophagy is a potential treatment for oxaliplatin-induced peripheral neuropathy.
Obesity worsens mitochondrial quality control and does not protect against skeletal muscle wasting in murine cancer cachexia.
Mitochondria transfer by platelet-derived microparticles regulates breast cancer bioenergetic states and malignant features.
Investigation of Mitochondrial Homeostasis Changes in Lens Epithelium of High-Myopic Cataract.
Imaging HOCl Generation during the Mitochondria Peripheral Fission with a Tailor-Made Fluorescent Probe.
A mitochondrial quality control mechanism reverses the phagosome maturation arrest caused by Mycobacterium tuberculosis.
The mitochondrial ATP synthase is a negative regulator of the mitochondrial permeability transition pore.
The critical roles of STING in mitochondrial homeostasis.
Organelle morphology and positioning orchestrate physiological and disease-associated processes.
Adipsin inhibits Irak2 mitochondrial translocation and improves fatty acid β-oxidation to alleviate diabetic cardiomyopathy.
Dihydroartemisinin suppresses glioma growth by repressing ERRα-mediated mitochondrial biogenesis.
Senecavirus a induces mitophagy to promote self-replication through direct interaction of 2C protein with K27-linked ubiquitinated TUFM catalyzed by RNF185.
ROS production by mitochondria: function or dysfunction?
Eif4enif1 haploinsufficiency disrupts oocyte mitochondrial dynamics and leads to subfertility.

J Proteome Res. 2023 Dec 08.

Multiomics Reveals Induction of Neuroblastoma SK-N-BE(2)C Cell Death by Mitochondrial Division Inhibitor 1 through Multiple Effects.

Wei-Hsuan Wang, Yi-Chun Kao, Chiao-Hui Hsieh, Shin-Yu Tsai, Chantal Hoi Yin Cheung, Hsuan-Cheng Huang, Hsueh-Fen Juan.

  Mitochondrial division inhibitor 1 (Mdivi-1) is a well-known synthetic compound aimed at inhibiting dynamin-related protein 1 (Drp1) to suppress mitochondrial fission, making it a valuable tool for studying mitochondrial dynamics. However, its specific effects beyond Drp1 inhibition remain to be confirmed. In this study, we employed integrative proteomics and phosphoproteomics to delve into the molecular responses induced by Mdivi-1 in SK-N-BE(2)C cells. A total of 3070 proteins and 1945 phosphorylation sites were identified, with 880 of them represented as phosphoproteins. Among these, 266 proteins and 97 phosphorylation sites were found to be sensitive to the Mdivi-1 treatment. Functional enrichment analysis unveiled their involvement in serine biosynthesis and extrinsic apoptotic signaling pathways. Through targeted metabolomics, we observed that Mdivi-1 enhanced intracellular serine biosynthesis while reducing the production of C24:1-ceramide. Within these regulated phosphoproteins, dynamic dephosphorylation of proteasome subunit alpha type 3 serine 250 (PSMA3-S250) occurred after Mdivi-1 treatment. Further site-directed mutagenesis experiments revealed that the dephosphorylation-deficient mutant PSMA3-S250A exhibited a decreased cell survival. This research confirms that Mdivi-1's inhibition of mitochondrial division leads to various side effects, ultimately influencing cell survival, rather than solely targeting Drp1 inhibition.

Keywords:  Mdivi-1; multiomics; neuroblastoma; phosphoproteome; proteome; targeted metabolome

DOI:  https://doi.org/10.1021/acs.jproteome.3c00566
Mitochondrion. 2023 Dec 11. pii: S1567-7249(23)00105-8. [Epub ahead of print] 101825

CMT2A-linked MFN2 mutation, T206I promotes mitochondrial hyperfusion and predisposes cells towards mitophagy.

Rajdeep Das, Sebabrata Maity, Palamou Das, Izaz Monir Kamal, Saikat Chakrabarti, Oishee Chakrabarti.

Mutations in Mitofusin2 (MFN2) associated with the pathology of the debilitating neuropathy Charcot-Marie-Tooth type 2A (CMT2A) are known to alter mitochondrial morphology. Previously, such mutations have been shown to elicit two diametrically opposite phenotypes - while some mutations have been causally linked to enhanced mitochondrial fragmentation, others have been shown to induce hyperfusion. Our study identifies one such MFN2 mutant, T206I that causes mitochondrial hyperfusion. Cells expressing this MFN2 mutant have elongated and interconnected mitochondria. T206I-MFN2 mutation in the GTPase domain increases MFN2 stability and renders cells susceptible to stress. We show that cells expressing T206I-MFN2 have a higher predisposition towards mitophagy under conditions of serum starvation. We also detect increased DRP1 recruitment onto the outer mitochondrial membrane, though the total DRP1 protein level remains unchanged. Here we have characterized a lesser studied CMT2A-linked MFN2 mutant to show that its presence affects mitochondrial morphology and homeostasis.

DOI: https://doi.org/10.1016/j.mito.2023.101825
Am J Physiol Lung Cell Mol Physiol. 2023 Dec 12.

Molecular Mechanisms Underlying TNFα Induced Mitochondrial Fragmentation in Human Airway Smooth Muscle Cells.

Debanjali Dasgupta, Sanjana Mahadev Bhat, Claire Creighton, Catherin Cortes, Philippe F Delmotte, Gary C Sieck.

  Tumor necrosis factor α (TNFa), a proinflammatory cytokine, plays a significant role in mediating the effects of acute inflammation in response to allergens, pollutants, and respiratory infections. Previously, we showed that acute exposure to TNFa induces mitochondrial fragmentation in human airway smooth muscle (hASM) cells, which is associated with increased expression of dynamin-related protein 1 (DRP1). Phosphorylation of DRP1 at serine 616 (pDRP1S616) promotes its translocation and binding to the outer mitochondrial membrane (OMM) and mediates mitochondrial fragmentation. Previously, we reported that TNFa exposure triggers protein unfolding and triggers an endoplasmic reticulum (ER) stress response involving phosphorylation of inositol-requiring enzyme 1α (pIRE1a) at serine 724 (pIRE1aS724) and subsequent splicing of X-box binding protein 1 (XBP1s) in hASM cells. We hypothesize that TNFa-mediated activation of the pIRE1aS724/XBP1s ER stress pathway in hASM cells transcriptionally activates genes that encode kinases responsible for pDRP1S616 phosphorylation. Using 3-D confocal imaging of MitoTracker green-labeled mitochondria, we found that TNFa treatment for 6 h induces mitochondrial fragmentation in hASM cells. We also confirmed that 6 h TNFa treatment activates the pIRE1a/XBP1s ER stress pathway. Using in silico analysis and ChIP assay, we showed that CDK1 and CDK5, kinases involved in the phosphorylation of pDRP1S616, are transcriptionally targeted by XBP1s. TNFa treatment increased the binding affinity of XBP1s on the promoter regions of CDK1 and CDK5, and this was associated with an increase in pDRP1S616 and mitochondria fragmentation. This study reveals a new underlying molecular mechanism for TNFa-induced mitochondrial fragmentation in hASM cells.

Keywords:  Airway smooth muscle; DRP1 phosphorylation; ER stress; airway inflammation; mitochondrial fragmentation

DOI:  https://doi.org/10.1152/ajplung.00198.2023
Environ Toxicol. 2023 Dec 14.

Cadmium-induced global DNA hypermethylation promoting mitochondrial dynamics dysregulation in hippocampal neurons.

Huixia Geng, Qihang An, Jie Song, Dongling He, Huimin Han, Lai Wang.

  Environmental cadmium exposure during pregnancy or adolescence can cause neurodevelopmental toxicity, lead to neurological impairment, and reduce cognitive abilities, such as learning and memory. However, the mechanisms by which cadmium causes neurodevelopmental toxicity and cognitive impairment are still not fully elucidated. This study used hippocampal neurons cultured in vitro to observe the impact of cadmium exposure on mitochondrial dynamics and apoptosis. Exposure to 5 μM cadmium causes degradation of hippocampal neuron cell bodies and axons, morphological destruction, low cell viability, and apoptosis increase. Cadmium exposure upregulates the expression of mitochondrial fission proteins Drp1 and Fis1, reduces the expression of mitochondrial fusion-related proteins MFN1, MFN2, and OPA1, as well as reduces the expression of PGC-1a. Mitochondrial morphology detection demonstrated that cadmium exposure changes the morphological structure of mitochondria in hippocampal neurons, increasing the number of punctate and granular mitochondria, reducing the number of tubular and reticular mitochondria, decreasing mitochondrial mass, dissipating mitochondrial membrane potential (ΔΨm), and reducing adenosine triphosphate (ATP) production. Cadmium exposure increases the global methylation level of the genome and upregulates the expression of DNMT1 and DNMT3α in hippocampal neurons. 5-Aza-CdR reduces cadmium-induced genome methylation levels in hippocampal neurons, increases the number of tubular and reticular mitochondria, and promotes cell viability. In conclusion, cadmium regulates the expression of mitochondrial dynamics-related proteins by increasing hippocampal neuron genome methylation, changing mitochondrial morphology and function, and exerting neurotoxic effects.

Keywords:  DNA methylation; cadmium; hippocampal neurons; mitochondrial dynamics

DOI:  https://doi.org/10.1002/tox.24083
Nat Commun. 2023 Dec 11. 14(1): 8187

GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis.

Qiang Zhu, Matthew E Combs, Juan Liu, Xue Bai, Wenbo B Wang, Laura E Herring, Jiandong Liu, Jason W Locasale, Dawn E Bowles, Ryan T Gross, Michelle Mendiola Pla, Christopher P Mack, Joan M Taylor.

The serine/threonine kinase, PINK1, and the E3 ubiquitin ligase, Parkin, are known to facilitate LC3-dependent autophagosomal encasement and lysosomal clearance of dysfunctional mitochondria, and defects in this process contribute to a variety of cardiometabolic and neurological diseases. Although recent evidence indicates that dynamic actin remodeling plays an important role in PINK1/Parkin-mediated mitochondrial autophagy (mitophagy), the underlying signaling mechanisms remain unknown. Here, we identify the RhoGAP GRAF1 (Arhgap26) as a PINK1 substrate that regulates mitophagy. GRAF1 promotes the release of damaged mitochondria from F-actin anchors, regulates mitochondrial-associated Arp2/3-mediated actin remodeling and facilitates Parkin-LC3 interactions to enhance mitochondria capture by autophagosomes. Graf1 phosphorylation on PINK1-dependent sites is dysregulated in human heart failure, and cardiomyocyte-restricted Graf1 depletion in mice blunts mitochondrial clearance and attenuates compensatory metabolic adaptations to stress. Overall, we identify GRAF1 as an enzyme that coordinates cytoskeletal and metabolic remodeling to promote cardioprotection.

DOI: https://doi.org/10.1038/s41467-023-43889-6
FASEB J. 2024 Jan;38(1): e23343

Caveolin-1 promotes mitochondrial health and limits mitochondrial ROS through ROCK/AMPK regulation of basal mitophagic flux.

Logan R Timmins, Milene Ortiz-Silva, Bharat Joshi, Y Lydia Li, Fiona H Dickson, Timothy H Wong, Kurt R Vandevoorde, Ivan R Nabi.

  Caveolin-1 (CAV1), the main structural component of caveolae, is phosphorylated at tyrosine-14 (pCAV1), regulates signal transduction, mechanotransduction, and mitochondrial function, and plays contrasting roles in cancer progression. We report that CRISPR/Cas9 knockout (KO) of CAV1 increases mitochondrial oxidative phosphorylation, increases mitochondrial potential, and reduces ROS in MDA-MB-231 triple-negative breast cancer cells. Supporting a role for pCAV1, these effects are reversed upon expression of CAV1 phosphomimetic CAV1 Y14D but not non-phosphorylatable CAV1 Y14F. pCAV1 is a known effector of Rho-associated kinase (ROCK) signaling and ROCK1/2 signaling mediates CAV1 promotion of increased mitochondrial potential and decreased ROS production in MDA-MB-231 cells. CAV1/ROCK control of mitochondrial potential and ROS is caveolae-independent as similar results were observed in PC3 prostate cancer cells lacking caveolae. Increased mitochondrial health and reduced ROS in CAV1 KO MDA-MB-231 cells were reversed by knockdown of the autophagy protein ATG5, mitophagy regulator PINK1 or the mitochondrial fission protein Drp1 and therefore due to mitophagy. Use of the mitoKeima mitophagy probe confirmed that CAV1 signaling through ROCK inhibited basal mitophagic flux. Activation of AMPK, a major mitochondrial homeostasis protein inhibited by ROCK, is inhibited by CAV1-ROCK signaling and mediates the increased mitochondrial potential, decreased ROS, and decreased basal mitophagy flux observed in wild-type MDA-MB-231 cells. CAV1 regulation of mitochondrial health and ROS in cancer cells therefore occurs via ROCK-dependent inhibition of AMPK. This study therefore links pCAV1 signaling activity at the plasma membrane with its regulation of mitochondrial activity and cancer cell metabolism through control of mitophagy.

Keywords:  AMPK; caveolin-1; mitochondria; mitophagy; reactive oxygen species; rho kinase

DOI:  https://doi.org/10.1096/fj.202201872RR
Sci Rep. 2023 Dec 07. 13(1): 21638

The interplay between sex, time of day, fasting status, and their impact on cardiac mitochondrial structure, function, and dynamics.

Mariame S Kane, Gloria A Benavides, Edie Osuma, Michelle S Johnson, Helen E Collins, Yecheng He, David Westbrook, Silvio H Litovsky, Kasturi Mitra, John C Chatham, Victor Darley-Usmar, Martin E Young, Jianhua Zhang.

Mitochondria morphology and function, and their quality control by mitophagy, are essential for heart function. We investigated whether these are influenced by time of the day (TOD), sex, and fed or fasting status, using transmission electron microscopy (EM), mitochondrial electron transport chain (ETC) activity, and mito-QC reporter mice. We observed peak mitochondrial number at ZT8 in the fed state, which was dependent on the intrinsic cardiac circadian clock, as hearts from cardiomyocyte-specific BMAL1 knockout (CBK) mice exhibit different TOD responses. In contrast to mitochondrial number, mitochondrial ETC activities do not fluctuate across TOD, but decrease immediately and significantly in response to fasting. Concurrent with the loss of ETC activities, ETC proteins were decreased with fasting, simultaneous with significant increases of mitophagy, mitochondrial antioxidant protein SOD2, and the fission protein DRP1. Fasting-induced mitophagy was lost in CBK mice, indicating a direct role of BMAL1 in regulating mitophagy. This is the first of its kind report to demonstrate the interactions between sex, fasting, and TOD on cardiac mitochondrial structure, function and mitophagy. These studies provide a foundation for future investigations of mitochondrial functional perturbation in aging and heart diseases.

DOI: https://doi.org/10.1038/s41598-023-49018-z
Cell Signal. 2023 Dec 11. pii: S0898-6568(23)00423-0. [Epub ahead of print] 111008

NOX4 alleviates breast cancer cell aggressiveness by co-ordinating mitochondrial turnover through PGC1α/Drp1 axis.

Deepali Bhadane, Dinisha Kamble, Mangesh Deval, Subhajit Das, Sandhya Sitasawad.

  Triple Negative Breast Cancer (TNBC) is a highly aggressive form of breast cancer, with few treatment options. This study investigates the complex molecular mechanism by which NADPH oxidase 4 (NOX4), a major ROS producer in mitochondria, affects the aggressiveness of luminal and triple-negative breast cancer cells (TNBCs). We found that NOX4 expression was differentially regulated in luminal and TNBC cells, with a positive correlation to their epithelial characteristics. Time dependent analysis revealed that TNBCs exhibits higher steady-state ROS levels than luminal cells, but NOX4 silencing increased ROS levels in luminal breast cancer cells and enhanced their ability to migrate and invade. In contrast, NOX4 over expression in TNBCs had the opposite effect. The mouse tail-vein experiment showed that the group injected with NOX4 silenced luminal cells had a higher number of lung metastases compared to the control group. Mechanistically, NOX4 enhanced PGC1α dependent mitochondrial biogenesis and attenuated Drp1-mediated mitochondrial fission in luminal breast cancer cells, leading to an increased mitochondrial mass and elongated mitochondrial morphology. Interestingly, NOX4 silencing increased mitochondrial ROS (mtROS) levels without affecting mitochondrial (Δψm) and cellular integrity. Inhibition of Drp1-dependent fission with Mdivi1 reversed the effect of NOX4-dependent mitochondrial biogenesis, dynamics, and migration of breast cancer cells. Our findings suggest that NOX4 expression diminishes from luminal to a triple negative state, accompanied by elevated ROS levels, which may modulate mitochondrial turnover to attain an aggressive phenotype. The study provides potential insights for targeted therapies for TNBCs.

Keywords:  Breast cancer aggressiveness; Drp1; NOX4; PGC1α; ROS; TNBC

DOI:  https://doi.org/10.1016/j.cellsig.2023.111008
Int J Mol Sci. 2023 Nov 27. pii: 16833. [Epub ahead of print]24(23):

Mitochondrial Dyshomeostasis as an Early Hallmark and a Therapeutic Target in Amyotrophic Lateral Sclerosis.

Natalia V Belosludtseva, Lyudmila A Matveeva, Konstantin N Belosludtsev.

  Amyotrophic lateral sclerosis (ALS) is a fatal multisystem disease characterized by progressive death of motor neurons, loss of muscle mass, and impaired energy metabolism. More than 40 genes are now known to be associated with ALS, which together account for the majority of familial forms of ALS and only 10% of sporadic ALS cases. To date, there is no consensus on the pathogenesis of ALS, which makes it difficult to develop effective therapy. Accumulating evidence indicates that mitochondria, which play an important role in cellular homeostasis, are the earliest targets in ALS, and abnormalities in their structure and functions contribute to the development of bioenergetic stress and disease progression. Mitochondria are known to be highly dynamic organelles, and their stability is maintained through a number of key regulatory pathways. Mitochondrial homeostasis is dynamically regulated via mitochondrial biogenesis, clearance, fission/fusion, and trafficking; however, the processes providing "quality control" and distribution of the organelles are prone to dysregulation in ALS. Here, we systematically summarized changes in mitochondrial turnover, dynamics, calcium homeostasis, and alterations in mitochondrial transport and functions to provide in-depth insights into disease progression pathways, which may have a significant impact on current symptomatic therapies and personalized treatment programs for patients with ALS.

Keywords:  SOD1; amyotrophic lateral sclerosis; bioenergetic stress; mitochondria; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dyshomeostasis; mitophagy; oxidative stress

DOI:  https://doi.org/10.3390/ijms242316833
Psychoneuroendocrinology. 2023 Nov 24. pii: S0306-4530(23)00661-3. [Epub ahead of print]160 106683

Mitochondrial morphology in the mouse adrenal cortex: Influence of chronic psychosocial stress.

Tamara Vega-Vásquez, Dominik Langgartner, Jennifer Y Wang, Stefan O Reber, Martin Picard, Carla Basualto-Alarcón.

  Mitochondria within the adrenal cortex play a key role in synthesizing steroid hormones. The adrenal cortex is organized in three functionally specialized zones (glomerulosa, fasciculata, and reticularis) that produce different classes of steroid hormones in response to various stimuli, including psychosocial stress. Given that the functions and morphology of mitochondria are dynamically related and respond to stress, we applied transmission electron microscopy (TEM) to examine potential differences in mitochondrial morphology under basal and chronic psychosocial stress conditions. We used the chronic subordinate colony housing (CSC) paradigm, a murine model of chronic psychosocial stress. Our findings quantitatively define how mitochondrial morphology differs among each of the three adrenal cortex zones under basal conditions, and show that chronic psychosocial stress mainly affected mitochondria in the zona glomerulosa, shifting their morphology towards the more typical glucocorticoid-producing zona fasciculata mitochondrial phenotype. Analysis of adrenocortical lipid droplets that provide cholesterol for steroidogenesis showed that chronic psychosocial stress altered lipid droplet diameter, without affecting droplet number or inter-organellar mitochondria-lipid droplet interactions. Together, our findings support the hypothesis that each adrenal cortex layer is characterized by morphologically distinct mitochondria and that this adrenal zone-specific mitochondrial morphology is sensitive to environmental stimuli, including chronic psychosocial stressors. Further research is needed to define the role of these stress-induced changes in mitochondrial morphology, particularly in the zona glomerulosa, on stress resilience and related behaviors.

Keywords:  Adrenal cortex; Chronic psychosocial stress; Electron microscopy; Lipid droplet; Mitochondria; Peridroplet mitochondria

DOI:  https://doi.org/10.1016/j.psyneuen.2023.106683
ACS Omega. 2023 Dec 05. 8(48): 45208-45223

DRP1: At the Crossroads of Dysregulated Mitochondrial Dynamics and Altered Cell Signaling in Cancer Cells.

Ankita Adhikary, Agradeep Mukherjee, Riddhi Banerjee, Shirisha Nagotu.

In the past decade, compelling evidence has accumulated that highlights the role of various subcellular structures in human disease conditions. Dysregulation of these structures greatly impacts cellular function and, thereby, disease conditions. One such organelle extensively studied for its role in several human diseases, especially cancer, is the mitochondrion. DRP1 is a GTPase that is considered the master regulator of mitochondrial fission and thereby also affects the proper functioning of the organelle. Altered signaling pathways are a distinguished characteristic of cancer cells. In this review, we aim to summarize our current understanding of the interesting crosstalk between the mitochondrial structure-function maintained by DRP1 and the signaling pathways that are affected in cancer cells. We highlight the structural aspects of DRP1, its regulation by various modifications, and the association of the protein with various cellular pathways altered in cancer. A better understanding of this association may help in identifying potential pharmacological targets for novel therapies in cancer.

DOI: https://doi.org/10.1021/acsomega.3c06547
Respir Res. 2023 Dec 13. 24(1): 310

Tom70-regulated mitochondrial biogenesis via TFAM improves hypoxia-induced dysfunction of pulmonary vascular endothelial cells and alleviates hypoxic pulmonary hypertension.

Lei Ma, Yanxia Wang, Xiaoqian Li, Zefang Wang, Bo Zhang, Ying Luo, Yousheng Wu, Zhichao Li, Wen Niu.

   BACKGROUND: Hypoxic pulmonary hypertension (HPH) is a common type of pulmonary hypertension and characterized by pulmonary vascular remodeling and constriction. A large number of studies have shown that pulmonary vascular endothelial cells (PVECs) dysfunction plays an important role in the initiation and development stages of HPH, but the mechanism of PVECs dysfunction after hypoxia remains unclear. In this study, we explored the exact mechanism of PVECs dysfunction after hypoxia.
METHODS: In vitro, we used primary cultured PVECs hypoxia model to mimic HPH injury. We detected the expressions of mitochondrial biogenesis markers, mitochondrial transcription factor A (TFAM) level inside mitochondria, mitochondrial quantity and function, and the components expressions of translocase of outer mitochondrial membrane (TOM) at 24 h after hypoxia. To explore the effects of Tom70 on mitochondrial biogenesis and functions of PVECs after hypoxia, Tom70 overexpression adenovirus was constructed, and the expressions of mitochondrial biogenesis markers, TFAM level inside mitochondria, mitochondrial quantity and function, and the functions of PVECs were detected. And in vivo, we used cre-dependent overexpression adenovirus of Tom70 in the Cdh5-CreERT2 mouse model of HPH to verify the role of upregulating PVECs Tom70 in improving HPH.
RESULTS: Hypoxia obviously increased the expressions of mitochondrial biogenesis markers for PGC-1α, NRF-1 and TFAM, but reduced the content of TFAM in mitochondria and the quantity and functions of mitochondria. In addition, only Tom70 expression among the TOM components was significantly decreased after hypoxia, and up-regulation of Tom70 significantly increased the content of TFAM in mitochondria of PVECs by transporting TFAM into mitochondria after hypoxia, enhanced the quantity and functions of mitochondria, improved the functions of PVECs, and ultimately alleviated HPH.
CONCLUSION: The findings of present study demonstrated that hypoxia induced the decreased expression of Tom70 in PVECs, reduced the mitochondrial biogenesis-associated TFAM protein transporting into mitochondria, inhibited mitochondrial biogenesis, caused PVECs injury, and prompted the formation of HPH. However, up-regulation of Tom70 abolished the hypoxia-induced injurious effects on PVECs and alleviated HPH.

Keywords:  Hypoxic pulmonary hypertension; Mitochondrial biogenesis; Pulmonary vascular endothelial cells; Translocase of outer mitochondrial membrane

DOI:  https://doi.org/10.1186/s12931-023-02631-y
Am J Physiol Cell Physiol. 2023 Dec 11.

Parkin-mediated mitophagy is a potential treatment for oxaliplatin-induced peripheral neuropathy.

Guoqing Zhao, Te Zhang, Jiannan Li, Longyun Li, Peng Chen, Chunlu Zhang, Kai Li, Cancan Cui.

  Oxaliplatin-induced peripheral nerve pain (OIPNP) is a common chemotherapy-related complication, but the mechanism is complex. Mitochondria are vital for cellular homeostasis and regulating oxidative stress. Parkin-mediated mitophagy is a cellular process that removes damaged mitochondria, exhibiting a protective effect in various diseases; however, its role in OIPNP remains unclear. In this study, we found that Parkin-mediated mitophagy was decreased, and reactive oxygen species (ROS) was upregulated in OIPNP rat dorsal root ganglion (DRG) in vivo and in PC12 cells stimulated with oxaliplatin (OXA) in vitro. Overexpression of Parkin indicated that OXA might cause mitochondrial and cell damage by inhibiting mitophagy. We also showed that salidroside (SAL) upregulated Parkin-mediated mitophagy to eliminate damaged mitochondria and promote PC12 cell survival. Knockdown of Parkin indicated that mitophagy is crucial for apoptosis and mitochondrial homeostasis in PC12 cells. In vivo study also demonstrated that SAL enhances Parkin-mediated mitophagy in the DRG and alleviates peripheral nerve injury and pain. These results suggest that Parkin-mediated mitophagy is involved in the pathogenesis of OIPNP and may be a potential therapeutic target for OIPNP.

Keywords:  Parkin; mitophagy; oxaliplatin; peripheral nerve pain; salidroside

DOI:  https://doi.org/10.1152/ajpcell.00276.2023
J Cachexia Sarcopenia Muscle. 2023 Dec 07.

Obesity worsens mitochondrial quality control and does not protect against skeletal muscle wasting in murine cancer cachexia.

Thomas D Cardaci, Brandon N VanderVeen, Brooke M Bullard, Sierra J McDonald, Christian A Unger, Reilly T Enos, Daping Fan, Kandy T Velázquez, Norma Frizzell, Espen E Spangenburg, E Angela Murphy.

   BACKGROUND: More than 650 million people are obese (BMI > 30) worldwide, which increases their risk for several metabolic diseases and cancer. While cachexia and obesity are at opposite ends of the weight spectrum, leading many to suggest a protective effect of obesity against cachexia, mechanistic support for obesity's benefit is lacking. Given that obesity and cachexia are both accompanied by metabolic dysregulation, we sought to investigate the impact of obesity on skeletal muscle mass loss and mitochondrial dysfunction in murine cancer cachexia.
METHODS: Male C57BL/6 mice were given a purified high fat or standard diet for 16 weeks before being implanted with 106 Lewis lung carcinoma (LLC) cells. Mice were monitored for 25 days, and hindlimb muscles were collected for cachexia indices and mitochondrial assessment via western blotting, high-resolution respirometry and transmission electron microscopy (TEM).
RESULTS: Obese LLC mice experienced significant tumour-free body weight loss similar to lean (-12.8% vs. -11.8%, P = 0.0001) but had reduced survival (33.3% vs. 6.67%, χ2 = 10.04, P = 0.0182). Obese LLC mice had reduced muscle weights (-24%, P < 0.0354) and mCSA (-16%, P = 0.0004) with similar activation of muscle p65 (P = 0.0337), and p38 (P = 0.0008). ADP-dependent coupled respiration was reduced in both Obese and Obese LLC muscle (-30%, P = 0.0072) consistent with reductions in volitional cage activity (-39%, P < 0.0001) and grip strength (-41%, P < 0.0001). TEM revealed stepwise reductions in intermyofibrillar and subsarcolemmal mitochondrial size with Obese (IMF: -37%, P = 0.0009; SS: -21%, P = 0.0101) and LLC (IMF: -40%, P = 0.0019; SS: -27%, P = 0.0383) mice. Obese LLC mice had increased pAMPK (T172; P = 0.0103) and reduced FIS1 (P = 0.0029) and DRP1 (P < 0.0001) mitochondrial fission proteins, which were each unchanged in Lean LLC. Further, mitochondrial TEM analysis revealed that Obese LLC mice had an accumulation of damaged and dysfunctional mitochondria (IMF: 357%, P = 0.0395; SS: 138%, P = 0.0174) in concert with an accumulation of p62 (P = 0.0328) suggesting impaired autophagy and clearance of damaged mitochondria. Moreover, we observed increases in electron lucent vacuoles only in Obese LLC muscle (IMF: 421%, P = 0.0260; SS: 392%, P = 0.0192), further supporting an accumulation of damaged materials that cannot be properly cleared in the obese cachectic muscle.
CONCLUSIONS: Taken together, these results demonstrate that obesity is not protective against cachexia and suggest exacerbated impairments to mitochondrial function and quality control with a particular disruption in the removal of damaged mitochondria. Our findings highlight the need for consideration of the severity of obesity and pre-existing metabolic conditions when determining the impact of weight status on cancer-induced cachexia and functional mitochondrial deficits.

Keywords:  Autophagy; High fat diet; Lewis lung carcinoma; Mitochondrial dysfunction; Mitophagy; Muscle atrophy

DOI:  https://doi.org/10.1002/jcsm.13391
Mol Cancer Res. 2023 Dec 12.

Mitochondria transfer by platelet-derived microparticles regulates breast cancer bioenergetic states and malignant features.

Vanessa Veilleux, Nicolas Pichaud, Luc H Boudreau, Gilles A Robichaud.

An increasing number of studies show that platelets as well as platelet-derived microparticles (PMPs) play significant roles in cancer malignancy and disease progression. Particularly, PMPs have the capacity to interact and internalize within target cells resulting in the transfer of their bioactive cargo, which can modulate the signaling and activation processes of recipient cells. We recently identified a new subpopulation of these vesicles (termed mitoMPs), which contain functional mitochondria. Given the predominant role of mitochondria in cancer cell metabolism and disease progression, we set out to investigate the impact of mitoMPs on breast cancer metabolic reprograming and phenotypic processes leading to malignancy. Interestingly, we observed that recipient cell permeability to PMP internalization varied among the breast cancer cell types evaluated in our study. Specifically, cells permissive to mitoMPs acquire mitochondrial-dependent functions, which stimulate increased cellular oxygen consumption rates and intracellular ATP production. In addition, cancer cells co-incubated with PMPs display enhanced malignant features in terms of migration and invasion. Most importantly, the cancer aggressive processes and notable metabolic plasticity induced by PMPs were highly dependent on the functional status of the mitoMP-packaged mitochondria. These findings characterize a new mechanism by which breast cancer cells acquire foreign mitochondria resulting in the gain of metabolic processes and malignant features. A better understanding of these mechanisms may provide therapeutic opportunities through PMP blockade to deprive cancer cells from resources vital in disease progression. Implications: We show that the transfer of foreign mitochondria by microparticles modulates recipient cancer cell metabolic plasticity, leading to greater malignant processes.

DOI: https://doi.org/10.1158/1541-7786.MCR-23-0329
Curr Eye Res. 2023 Dec 11. 1-10

Investigation of Mitochondrial Homeostasis Changes in Lens Epithelium of High-Myopic Cataract.

Chenghao Sun, Pengfei Li, Guowei Zhang, Wenjing Geng, Congyu Wang, Sijie Bao, Xi Liu, Min Ji, Huaijin Guan.

   PURPOSE: High myopia is demonstrated as a pathogenic factor for nuclear cataract. The main mechanism of high-myopia cataracts (HMC) is oxidative damage, which causes mitochondrial homeostasis imbalance. This study aimed to explore the mitochondrial homeostasis alterations in lens epithelial cells (LECs) of HMC.
METHODS: The lens epithelium tissues of 20 patients with HMC and 20 control subjects with age-related cataracts (ARC) were collected. The real-time quantitative PCR and western blot assays were performed for gene expressions. Immunofluorescence (IF) assays were performed for mitochondrial marker TOM20, DNA damage marker 15A3, and autophagosome marker LC3. Transmission electron microscopy (TEM) was used to observe the changes in mitochondria morphology. Mitochondrial ROS, and mitochondrial membrane potential were detected by MitoSOX fluorescence, and JC-1 MitoMP staining, respectively. Rat lenses cultured in vitro were pretreated with CCCP and H2O2 (10 and 400 µM) for 24 h.
RESULTS: The copy number of mtDNA was decreased in HMC patients compared to the ARC patients. Increased mitochondrial-oriented oxidative stress response was detected in LECs of HMC compared to that of ARC. Altered expressions of mitochondrial homeostasis and mitophagy markers, including TFAM, PGC1α, MFN1, MFN2, Drp1, PINK1, Parkin and LC3, were found in HMC patients. Reciprocally, no significant differences in the expression of BNIP3 and FUNDC1 were found between HMC and ARC patients. Importantly, TEM revealed that the obvious mitochondrial fission and mitophagy phenomena occur in the LECs of HMC patients compared to the ARC patients. Moreover, CCCP aggreated the mitoROS production and depolarized mitochondrial membrane potential in the H2O2-treated human lens epithelial cells line (SRA01/04); Most important, rat lens organ culture experiments indicated a significant increase in H2O2-induced lens opacity following mitochondrial uncoupling CCCP treatment.
CONCLUSION: This study has identified for the first time the abnormal mitochondrial homeostasis in HMC, and provide a new perspective on the potential mechanisms of HMC, which occurs earlier and at a higher incidence rate than ARC.

Keywords:  Cataract; high myopic; mitochondrial homeostasis; oxidative damage

DOI:  https://doi.org/10.1080/02713683.2023.2276679
Anal Chem. 2023 Dec 12.

Imaging HOCl Generation during the Mitochondria Peripheral Fission with a Tailor-Made Fluorescent Probe.

Haolin Zhang, Ya Liu, Xiaofan Zhang, Huimin Ma, Wen Shi, Xiaohua Li.

Mitochondrial fission is a highly regulated process that can affect metabolism, proliferation, and apoptosis. Division at the periphery enables damaged material to be shed into smaller mitochondria destined for mitophagy, which is found preceded by increased Ca2+ and reactive oxygen species, as well as reduced membrane potential and pH. However, the variation of hypochlorous acid (HOCl) during the peripheral fission has not been well studied, and the existing fluorescent probes are unsuitable for detecting mitochondrial HOCl because of the 0.8-fold decreased pH during this process. Herein, we design a novel CCS (changeable π-conjugation system)-based probe (ON-mito) with a dibenzo[1,4]oxazepine core, which can selectively react with HOCl at pH 6.4, generating an oxazine-containing product that emits at 660 nm. The capability of ON-mito for imaging the HOCl generation in HeLa cells during mitophagy is demonstrated under weakly acidic condition. Further, with ON-mito, we find for the first time a burst increase of the mitochondrial HOCl in COS-7 cells during peripheral fission, which may serve as an important indicator of this process. Probe ON-mito may be useful for studying mitochondrial damage under diverse conditions.

DOI: https://doi.org/10.1021/acs.analchem.3c04215
bioRxiv. 2023 Dec 01. pii: 2023.12.01.569475. [Epub ahead of print]

A mitochondrial quality control mechanism reverses the phagosome maturation arrest caused by Mycobacterium tuberculosis.

Surbhi Verma, Mrinmoy Das, Raman D Sharma, Vikas Yadav, Shweta Thakur, Priya Sharma, Mardiana Marzuki, Shihui Foo, Giulia M Piperno, Mehak Z Khan, Babu Mathew, Meenu Bajpai, Jaswinder Singh Maras, Shanshan Howland, Sovan Sarkar, Federica Benvenuti, Amit Singh, Vinay Nandicoori, Amit Singhal, Dhiraj Kumar.

Phagosome maturation arrest (PMA) imposed by Mycobacterium tuberculosis ( Mtb ) is a classic tool that helps Mtb evade macrophage anti-bacterial responses. The exclusion of RAB7, a small GTPase, from Mtb -phagosomes underscores PMA. Here we report an unexpected mechanism that triggers crosstalk between the mitochondrial quality control (MQC) and the phagosome maturation pathways that reverses the PMA. CRISPR-mediated p62/SQSTM1 depletion ( p62 KD ) blocks mitophagy flux without impacting mitochondrial quality. In p62 KD cells, Mtb growth and survival are diminished, mainly through witnessing an increasingly oxidative environment and increased lysosomal targeting. The lysosomal targeting of Mtb is facilitated by enhanced TOM20 + mitochondria-derived vesicles (MDVs) biogenesis, a key MQC mechanism. In p62 KD cells, TOM20 + -MDVs biogenesis is MIRO1/MIRO2-dependent and delivered to lysosomes for degradation in a RAB7-dependent manner. Upon infection in p62 KD cells, TOM20 + -MDVs get extensively targeted to Mtb -phagosomes, inadvertently facilitating RAB7 recruitment, PMA reversal and lysosomal targeting of Mtb . Triggering MQC collapse in p62 KD cells further diminishes Mtb survival signifying cooperation between redox- and lysosome-mediated mechanisms. The MQC-anti-bacterial pathway crosstalk could be exploited for host-directed anti-tuberculosis therapies.

DOI: https://doi.org/10.1101/2023.12.01.569475
Proc Natl Acad Sci U S A. 2023 Dec 19. 120(51): e2303713120

The mitochondrial ATP synthase is a negative regulator of the mitochondrial permeability transition pore.

Ryan Pekson, Felix G Liang, Joshua L Axelrod, Jaehoon Lee, Dongze Qin, Andre J H Wittig, Victor M Paulino, Min Zheng, Pablo M Peixoto, Richard N Kitsis.

  The mitochondrial permeability transition pore (mPTP) is a channel in the inner mitochondrial membrane whose sustained opening in response to elevated mitochondrial matrix Ca2+ concentrations triggers necrotic cell death. The molecular identity of mPTP is unknown. One proposed candidate is the mitochondrial ATP synthase, whose canonical function is to generate most ATP in multicellular organisms. Here, we present mitochondrial, cellular, and in vivo evidence that, rather than serving as mPTP, the mitochondrial ATP synthase inhibits this pore. Our studies confirm previous work showing persistence of mPTP in HAP1 cell lines lacking an assembled mitochondrial ATP synthase. Unexpectedly, however, we observe that Ca2+-induced pore opening is markedly sensitized by loss of the mitochondrial ATP synthase. Further, mPTP opening in cells lacking the mitochondrial ATP synthase is desensitized by pharmacological inhibition and genetic depletion of the mitochondrial cis-trans prolyl isomerase cyclophilin D as in wild-type cells, indicating that cyclophilin D can modulate mPTP through substrates other than subunits in the assembled mitochondrial ATP synthase. Mitoplast patch clamping studies showed that mPTP channel conductance was unaffected by loss of the mitochondrial ATP synthase but still blocked by cyclophilin D inhibition. Cardiac mitochondria from mice whose heart muscle cells we engineered deficient in the mitochondrial ATP synthase also demonstrate sensitization of Ca2+-induced mPTP opening and desensitization by cyclophilin D inhibition. Further, these mice exhibit strikingly larger myocardial infarctions when challenged with ischemia/reperfusion in vivo. We conclude that the mitochondrial ATP synthase does not function as mPTP and instead negatively regulates this pore.

Keywords:  mitochondrial ATP synthase; mitochondrial permeability transition pore; necrosis

DOI:  https://doi.org/10.1073/pnas.2303713120
Biochem Pharmacol. 2023 Dec 10. pii: S0006-2952(23)00531-2. [Epub ahead of print] 115938

The critical roles of STING in mitochondrial homeostasis.

Shishi Zou, Bo Wang, Ke Yi, Dandan Su, Yukai Chen, Ning Li, Qing Geng.

  The stimulator of interferon genes (STING) is a crucial signaling hub in the immune system's antiviral and antimicrobial defense by detecting exogenous and endogenous DNA. The multifaceted functions of STING have been uncovered gradually during past decades, including homeostasis maintenance and overfull immunity or inflammation induction. However, the subcellular regulation of STING and mitochondria is poorly understood. The main functions of STING are outlined in this review. Moreover, we discuss how mitochondria and STING interact through multiple mechanisms, including the release of mitochondrial DNA (mtDNA), modulation of mitochondria-associated membrane (MAM) and mitochondrial dynamics, alterations in mitochondrial metabolism, regulation of reactive oxygen species (ROS) production, and mitochondria-related cell death. Finally, we discuss how STING is crucial to disease development, providing a novel perspective on its role in cellular physiology and pathology.

Keywords:  Cell death; Innate immunity; Mitochondrial dynamics; Mitochondrial metabolism; MtDNA; STING

DOI:  https://doi.org/10.1016/j.bcp.2023.115938
Curr Opin Cell Biol. 2023 Dec 13. pii: S0955-0674(23)00142-4. [Epub ahead of print]86 102293

Organelle morphology and positioning orchestrate physiological and disease-associated processes.

Katerina Jerabkova-Roda, Rituraj Marwaha, Tamal Das, Jacky G Goetz.

In cells, organelles are distributed nonrandomly to regulate cells' physiological and disease-associated processes. Based on their morphology, position within the cell, and contacts with other organelles, they exert different biological functions. Endo-lysosomes are critical cell metabolism and nutrient-sensing regulators modulating cell growth and cellular adaptation in response to nutrient availability. Their spatial distribution is intimately linked to their function. In this review, we will discuss the role of endolysosomes under physiological conditions and in the context of cancer progression, with a special focus on their morphology, the molecular mechanisms determining their subcellular position, and the contacts they form with other organelles. We aim to highlight the relationship between cell architecture and cell function and its impact on maintaining organismal homeostasis.

DOI: https://doi.org/10.1016/j.ceb.2023.102293
Mil Med Res. 2023 Dec 11. 10(1): 63

Adipsin inhibits Irak2 mitochondrial translocation and improves fatty acid β-oxidation to alleviate diabetic cardiomyopathy.

Meng-Yuan Jiang, Wan-Rong Man, Xue-Bin Zhang, Xiao-Hua Zhang, Yu Duan, Jie Lin, Yan Zhang, Yang Cao, De-Xi Wu, Xiao-Fei Shu, Lei Xin, Hao Wang, Xiao Zhang, Cong-Ye Li, Xiao-Ming Gu, Xuan Zhang, Dong-Dong Sun.

   BACKGROUND: Diabetic cardiomyopathy (DCM) causes the myocardium to rely on fatty acid β-oxidation for energy. The accumulation of intracellular lipids and fatty acids in the myocardium usually results in lipotoxicity, which impairs myocardial function. Adipsin may play an important protective role in the pathogenesis of DCM. The aim of this study is to investigate the regulatory effect of Adipsin on DCM lipotoxicity and its molecular mechanism.
METHODS: A high-fat diet (HFD)-induced type 2 diabetes mellitus model was constructed in mice with adipose tissue-specific overexpression of Adipsin (Adipsin-Tg). Liquid chromatography-tandem mass spectrometry (LC-MS/MS), glutathione-S-transferase (GST) pull-down technique, Co-immunoprecipitation (Co-IP) and immunofluorescence colocalization analyses were used to investigate the molecules which can directly interact with Adipsin. The immunocolloidal gold method was also used to detect the interaction between Adipsin and its downstream modulator.
RESULTS: The expression of Adipsin was significantly downregulated in the HFD-induced DCM model (P < 0.05). Adipose tissue-specific overexpression of Adipsin significantly improved cardiac function and alleviated cardiac remodeling in DCM (P < 0.05). Adipsin overexpression also alleviated mitochondrial oxidative phosphorylation function in diabetic stress (P < 0.05). LC-MS/MS analysis, GST pull-down technique and Co-IP studies revealed that interleukin-1 receptor-associated kinase-like 2 (Irak2) was a downstream regulator of Adipsin. Immunofluorescence analysis also revealed that Adipsin was co-localized with Irak2 in cardiomyocytes. Immunocolloidal gold electron microscopy and Western blotting analysis indicated that Adipsin inhibited the mitochondrial translocation of Irak2 in DCM, thus dampening the interaction between Irak2 and prohibitin (Phb)-optic atrophy protein 1 (Opa1) on mitochondria and improving the structural integrity and function of mitochondria (P < 0.05). Interestingly, in the presence of Irak2 knockdown, Adipsin overexpression did not further alleviate myocardial mitochondrial destruction and cardiac dysfunction, suggesting a downstream role of Irak2 in Adipsin-induced responses (P < 0.05). Consistent with these findings, overexpression of Adipsin after Irak2 knockdown did not further reduce the accumulation of lipids and their metabolites in the cardiac myocardium, nor did it enhance the oxidation capacity of cardiomyocytes expose to palmitate (PA) (P < 0.05). These results indicated that Irak2 may be a downstream regulator of Adipsin.
CONCLUSIONS: Adipsin improves fatty acid β-oxidation and alleviates mitochondrial injury in DCM. The mechanism is related to Irak2 interaction and inhibition of Irak2 mitochondrial translocation.

Keywords:  Diabetic cardiomyopathy; Fatty acid β-oxidation; Mitochondrial function; Mitochondrial translocation

DOI:  https://doi.org/10.1186/s40779-023-00493-5
Mol Cell Biochem. 2023 Dec 11.

Dihydroartemisinin suppresses glioma growth by repressing ERRα-mediated mitochondrial biogenesis.

Wenxin Zhang, Yan Wang, Lu Chen, Haifei Chen, Huijie Qi, Yong Zheng, Yongli Du, Liudi Zhang, Tianxiao Wang, Qunyi Li.

  Malignant gliomas are an exceptionally lethal form of cancer with limited treatment options. Dihydroartemisinin (DHA), a sesquiterpene lactone antimalarial compound, has demonstrated therapeutic effects in various solid tumors. In our study, we aimed to investigate the mechanisms underlying the anticancer effects of DHA in gliomas. To explore the therapeutic and molecular mechanisms of DHA, we employed various assays, including cell viability, flow cytometry, mitochondrial membrane potential, glucose uptake and glioma xenograft models. Our data demonstrated that DHA significantly inhibited glioma cell proliferation in both temozolomide-resistant cells and glioma stem-like cells. We found that DHA-induced apoptosis occurred via the mitochondria-mediated pathway by initiating mitochondrial dysfunction before promoting apoptosis. Moreover, we discovered that DHA treatment substantially reduced the expression of the mitochondrial biogenesis-related gene, ERRα, in glioma cells. And the ERRα pathway is a critical target in treating glioma with DHA. Our results also demonstrated that the combination of DHA and temozolomide synergistically inhibited the proliferation of glioma cells. In vivo, DHA treatment remarkably extended survival time in mice bearing orthotopic glioblastoma xenografts. Thus, our findings suggest that DHA has a novel role in modulating cancer cell metabolism and suppressing glioma progression by activating the ERRα-regulated mitochondrial apoptosis pathway.

Keywords:  Dihydroartemisinin; Estrogen-related receptor alpha; Glioma; Mitochondrial apoptosis; Temozolomide resistant

DOI:  https://doi.org/10.1007/s11010-023-04892-z
Autophagy. 2023 Dec 12.

Senecavirus a induces mitophagy to promote self-replication through direct interaction of 2C protein with K27-linked ubiquitinated TUFM catalyzed by RNF185.

Meirong Chen, Xin Zhang, Fanshu Kong, Peng Gao, Xinna Ge, Lei Zhou, Jun Han, Xin Guo, Yongning Zhang, Hanchun Yang.

  Senecavirus A (SVA) is a newly emerging picornavirus associated with swine vesicular lesions and neonatal mortality, threatening the global pig industry. Despite sustained efforts, the molecular mechanisms of SVA pathogenesis have not yet been fully elucidated. Here, we demonstrate for the first time that SVA infection can induce complete mitophagy in host cells, which depends on SVA replication. Mitophagy has been subsequently proven to promote SVA replication in host cells. Genome-wide screening of SVA proteins involved in inducing mitophagy showed that although VP2, VP3, 2C, and 3A proteins can independently induce mitophagy, only the 2C protein mediates mitophagy through direct interaction with TUFM (Tu translation elongation factor, mitochondrial). The glutamic acids at positions 196 and 211 of TUFM were shown to be two key sites for its interaction with 2C protein. Moreover, TUFM was discovered to interact directly with BECN1 and indirectly with the ATG12-ATG5 conjugate. Further experiments revealed that TUFM needs to undergo ubiquitination modification before being recognized by the macroautophagy/autophagy receptor protein SQSTM1/p62, and E3 ubiquitin ligase RNF185 catalyzes K27-linked polyubiquitination of TUFM through the interaction between RNF185's transmembrane domain 1 and TUFM to initiate SVA-induced mitophagy. The ubiquitinated TUFM is recognized and bound by SQSTM1, which in turn interacts with MAP1LC3/LC3, thereby linking the 2C-anchored mitochondria to the phagophore for sequestration into mitophagosomes, which ultimately fuse with lysosomes to achieve complete mitophagy. Overall, our results elucidated the molecular mechanism by which SVA induces mitophagy to promote self-replication and provide new insights into SVA pathogenesis.

Keywords:  2C protein; RNF185; SVA; TUFM; mitophagy; replication

DOI:  https://doi.org/10.1080/15548627.2023.2293442
Oncogene. 2023 Dec 11.

ROS production by mitochondria: function or dysfunction?

Flavio R Palma, Benjamin N Gantner, Marcelo J Sakiyama, Cezar Kayzuka, Sanjeev Shukla, Riccardo Lacchini, Brian Cunniff, Marcelo G Bonini.

In eukaryotic cells, ATP generation is generally viewed as the primary function of mitochondria under normoxic conditions. Reactive oxygen species (ROS), in contrast, are regarded as the by-products of respiration, and are widely associated with dysfunction and disease. Important signaling functions have been demonstrated for mitochondrial ROS in recent years. Still, their chemical reactivity and capacity to elicit oxidative damage have reinforced the idea that ROS are the products of dysfunctional mitochondria that accumulate during disease. Several studies support a different model, however, by showing that: (1) limited oxygen availability results in mitochondria prioritizing ROS production over ATP, (2) ROS is an essential adaptive mitochondrial signal triggered by various important stressors, and (3) while mitochondria-independent ATP production can be easily engaged by most cells, there is no known replacement for ROS-driven redox signaling. Based on these observations and other evidence reviewed here, we highlight the role of ROS production as a major mitochondrial function involved in cellular adaptation and stress resistance. As such, we propose a rekindled view of ROS production as a primary mitochondrial function as essential to life as ATP production itself.

DOI: https://doi.org/10.1038/s41388-023-02907-z
Development. 2023 Dec 01. pii: dev202151. [Epub ahead of print]150(23):

Eif4enif1 haploinsufficiency disrupts oocyte mitochondrial dynamics and leads to subfertility.

Yuxi Ding, Zequn He, Yanwei Sha, Kehkooi Kee, Lin Li.

  Infertility affects couples worldwide. Premature ovarian insufficiency (POI) refers to loss of ovarian function before 40 years of age and is a contributing factor to infertility. Several case studies have reported dominant-inherited POI symptoms in families with heterozygous EIF4ENIF1 (4E-T) mutations. However, the effects of EIF4ENIF1 haploinsufficiency have rarely been studied in animal models to reveal the underlying molecular changes related to infertility. Here, we demonstrate that Eif4enif1 haploinsufficiency causes mouse subfertility, impairs oocyte maturation and partially arrests early embryonic development. Using dual-omic sequencing, we observed that Eif4enif1 haploinsufficiency significantly altered both transcriptome and translatome in mouse oocytes, by which we further revealed oocyte mitochondrial hyperfusion and mitochondria-associated ribonucleoprotein domain distribution alteration in Eif4enif1-deficient oocytes. This study provides new insights into the molecular mechanisms underlying clinical fertility failure and new avenues to pursue new therapeutic targets to address infertility.

Keywords:   Eif4enif1 ; Fertility; Mitochondrial dynamics; Mouse; Oocyte; RBP; Translation

DOI:  https://doi.org/10.1242/dev.202151