bims-midtic 2023-09-03 papers

bims-midtic

Biomed News

on Mitochondrial dynamics and trafficking in cells

Issue of 2023‒09‒03
eighteen papers selected by
Omkar Joshi, Turku Bioscience

Unveiling the potential of mitochondrial dynamics as a therapeutic strategy for acute kidney injury.
Inhibition of mitochondrial fusion via SIRT1/PDK2/PARL axis breaks mitochondrial metabolic plasticity and sensitizes cancer cells to glucose restriction therapy.
Promoting mitochondrial dynamic equilibrium attenuates sepsis-induced acute lung injury by inhibiting pro-inflammatory polarization of alveolar macrophages.
Restoration of mitochondrial structure and function within Helicobacter pylori VacA intoxicated cells.
IQGAP1 mediates the communication between the nucleus and the mitochondria via NDUFS4 alternative splicing.
Ruscogenin Alleviates Myocardial Ischemia via Myosin IIA-Dependent Mitochondrial Fusion and Fission Balance.
Effects of phosphorylation on Drp1 activation by its receptors, actin, and cardiolipin.
Impaired age-associated mitochondrial translation is mitigated by exercise and PGC-1α.
The three-dimensional conformation and activity of mitochondria in syncytial male germ line-cysts of medicinal leeches.
Upregulated Mitochondrial Dynamics Is Responsible for the Procatabolic Changes of Chondrocyte Induced by α2-Adrenergic Signal Activation.
An mTRAN-mRNA interaction mediates mitochondrial translation initiation in plants.
Pannexin 1 targets mitophagy to mediate renal ischemia/reperfusion injury.
Triaging of ⍺-helical proteins to the mitochondrial outer membrane by distinct chaperone machinery based on substrate topology.
An interactive deep learning-based approach reveals mitochondrial cristae topologies.
Mechanical stimulation from the surrounding tissue activates mitochondrial energy metabolism in Drosophila differentiating germ cells.
Beyond the TCA cycle: new insights into mitochondrial calcium regulation of oxidative phosphorylation.
A dynamic actin cytoskeleton is required to prevent constitutive VDAC-dependent MAPK signalling and aberrant lipid homeostasis.
Curcumin induces mitophagy by promoting mitochondrial succinate dehydrogenase activity and sensitizes human papillary thyroid carcinoma BCPAP cells to radioiodine treatment.

Front Cell Dev Biol. 2023 ;11 1244313

Unveiling the potential of mitochondrial dynamics as a therapeutic strategy for acute kidney injury.

Yajie Hao, Limei Zhao, Jing Yu Zhao, Xiutao Han, Xiaoshuang Zhou.

  Acute Kidney Injury (AKI), a critical clinical syndrome, has been strongly linked to mitochondrial malfunction. Mitochondria, vital cellular organelles, play a key role in regulating cellular energy metabolism and ensuring cell survival. Impaired mitochondrial function in AKI leads to decreased energy generation, elevated oxidative stress, and the initiation of inflammatory cascades, resulting in renal tissue damage and functional impairment. Therefore, mitochondria have gained significant research attention as a potential therapeutic target for AKI. Mitochondrial dynamics, which encompass the adaptive shifts of mitochondria within cellular environments, exert significant influence on mitochondrial function. Modulating these dynamics, such as promoting mitochondrial fusion and inhibiting mitochondrial division, offers opportunities to mitigate renal injury in AKI. Consequently, elucidating the mechanisms underlying mitochondrial dynamics has gained considerable importance, providing valuable insights into mitochondrial regulation and facilitating the development of innovative therapeutic approaches for AKI. This comprehensive review aims to highlight the latest advancements in mitochondrial dynamics research, provide an exhaustive analysis of existing studies investigating the relationship between mitochondrial dynamics and acute injury, and shed light on their implications for AKI. The ultimate goal is to advance the development of more effective therapeutic interventions for managing AKI.

Keywords:  acute kidney injury; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; therapeutic targets

DOI:  https://doi.org/10.3389/fcell.2023.1244313
Biomed Pharmacother. 2023 Aug 24. pii: S0753-3322(23)01133-2. [Epub ahead of print]166 115342

Inhibition of mitochondrial fusion via SIRT1/PDK2/PARL axis breaks mitochondrial metabolic plasticity and sensitizes cancer cells to glucose restriction therapy.

Yongjian Guo, Chengju Luo, Yuening Sun, Wenjing Guo, Ruitian Zhang, Xin Zhang, Xue Ke, Libin Wei.

  Mitochondria dynamically change their morphology via fusion and fission, a process called mitochondrial dynamics. Dysregulated mitochondrial dynamics respond rapidly to metabolic cues, and are linked to the initiation and progression of diverse human cancers. Metabolic adaptations significantly contribute to tumor development and escape from tissue homeostatic defenses. In this work, we identified oroxylin A (OA), a dual GLUT1/mitochondrial fusion inhibitor, which restricted glucose catabolism of hepatocellular carcinoma cells and simultaneously inhibited mitochondrial fusion by disturbing SIRT1/PDK2/PARL axis. Based the dual action of OA in metabolic regulation and mitochondrial dynamics, further results revealed that mitochondrial functional status and spare respiratory capacity (SRC) of cancer cells had a close correlation with mitochondrial metabolic plasticity, and played important roles in the susceptibility to cancer therapy aiming at glucose restriction. Cancer cells with healthy mitochondria and high SRC exhibit greater metabolic flexibility and higher resistance to GLUT1 inhibitors. This phenomenon is attributed to the fact that high SRC cells fuse mitochondria in response to glucose restriction, enhancing tolerance to energy deficiency, but undergo less mitochondrial oxidative stress compared to low SRC cells. Thus, inhibiting mitochondrial fusion breaks mitochondrial metabolic plasticity and increases cancer cell susceptibility to glucose restriction therapy. Collectively, these finding indicate that combining a GLUT1 inhibitor with a mitochondrial fusion inhibitor can work synergistically in cancer therapy and, more broadly, suggest that the incorporations of mitochondrial dynamics and metabolic regulation may become the targetable vulnerabilities bypassing the genotypic heterogeneity of multiple malignancies.

Keywords:  Glucose restriction; Mitochondrial fusion; Mitochondrial metabolic plasticity; Oroxylin A

DOI:  https://doi.org/10.1016/j.biopha.2023.115342
Shock. 2023 Aug 22.

Promoting mitochondrial dynamic equilibrium attenuates sepsis-induced acute lung injury by inhibiting pro-inflammatory polarization of alveolar macrophages.

Maomao Sun, Zhenhua Zeng, Gege Xu, Sheng An, Zhiya Deng, Ran Cheng, Yi Yao, Junjie Wu, Hongbin Hu, Qiaobing Huang, Jie Wu.

ABSTRACT: Sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is characterized by widespread pulmonary inflammation and immune response, in which pro-inflammatory polarization of alveolar macrophages (AMs) plays an important role. Mitochondria are the key intracellular signaling platforms regulating immune cell responses. Moreover, accumulating evidence suggests that the mitochondrial dynamics of macrophages are imbalanced in sepsis and severe ALI/ARDS. However, the functional significance of mitochondrial dynamics of AMs in septic ALI/ARDS remains largely unknown, and whether it regulates the polarized phenotype of AMs is also unclear. Here, we demonstrated that the mitochondrial dynamics of AMs are imbalanced, manifested by impaired mitochondrial fusion, increased fission and mitochondrial cristae remodeling, both in septic models and ARDS patients. However, suppressing excessive mitochondrial fission with Mdivi-1 or promoting mitochondrial fusion with PM1 to maintain mitochondrial dynamic equilibrium in AMs could inhibit the polarization of AMs into pro-inflammatory phenotype and attenuate sepsis-induced ALI. These data suggest that mitochondrial dynamic imbalance mediates altered polarization of AMs and exacerbates sepsis-induced ALI. This study provides new insights into the underlying mechanisms of sepsis-induced ALI, suggesting the possibility of identifying future drug targets from the perspective of mitochondrial dynamics in AMs.

DOI: https://doi.org/10.1097/SHK.0000000000002206
Adv Microbiol. 2023 Aug;13(8): 399-419

Restoration of mitochondrial structure and function within Helicobacter pylori VacA intoxicated cells.

Robin L Holland, Kristopher D Bosi, Ami Y Seeger, Steven R Blanke.

  The Helicobacter pylori vacuolating cytotoxin (VacA) is an intracellular, mitochondrial-targeting exotoxin that rapidly causes mitochondrial dysfunction and fragmentation. Although VacA targeting of mitochondria has been reported to alter overall cellular metabolism, there is little known about the consequences of extended exposure to the toxin. Here, we describe studies to address this gap in knowledge, which have revealed that mitochondrial dysfunction and fragmentation are followed by a time-dependent recovery of mitochondrial structure, mitochondrial transmembrane potential, and cellular ATP levels. Cells exposed to VacA also initially demonstrated a reduction in oxidative phosphorylation, as well as increase in compensatory aerobic glycolysis. These metabolic alterations were reversed in cells with limited toxin exposure, congruent with the recovery of mitochondrial transmembrane potential and the absence of cytochrome c release from the mitochondria. Taken together, these results are consistent with a model that mitochondrial structure and function are restored in VacA-intoxicated cells.

Keywords:  ATP; Helicobacter pylori; VacA; mitochondria; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial fission; mitochondrial transmembrane potential; oxidative phosphorylation; vacuolating cytotoxin

DOI:  https://doi.org/10.4236/aim.2023.138026
NAR Cancer. 2023 Sep;5(3): zcad046

IQGAP1 mediates the communication between the nucleus and the mitochondria via NDUFS4 alternative splicing.

Vasiliki Papadaki, Zoi Erpapazoglou, Maria Kokkori, Malgorzata Ewa Rogalska, Myrto Potiri, Andrada Birladeanu, Eleni N Tsakiri, Hassan Ashktorab, Duane T Smoot, Katerina Papanikolopoulou, Martina Samiotaki, Panagiota Kafasla.

Constant communication between mitochondria and nucleus ensures cellular homeostasis and adaptation to mitochondrial stress. Anterograde regulatory pathways involving a large number of nuclear-encoded proteins control mitochondrial biogenesis and functions. Such functions are deregulated in cancer cells, resulting in proliferative advantages, aggressive disease and therapeutic resistance. Transcriptional networks controlling the nuclear-encoded mitochondrial genes are known, however alternative splicing (AS) regulation has not been implicated in this communication. Here, we show that IQGAP1, a scaffold protein regulating AS of distinct gene subsets in gastric cancer cells, participates in AS regulation that strongly affects mitochondrial respiration. Combined proteomic and RNA-seq analyses of IQGAP1KO and parental cells show that IQGAP1KO alters an AS event of the mitochondrial respiratory chain complex I (CI) subunit NDUFS4 and downregulates a subset of CI subunits. In IQGAP1KO cells, CI intermediates accumulate, resembling assembly deficiencies observed in patients with Leigh syndrome bearing NDUFS4 mutations. Mitochondrial CI activity is significantly lower in KO compared to parental cells, while exogenous expression of IQGAP1 reverses mitochondrial defects of IQGAP1KO cells. Our work sheds light to a novel facet of IQGAP1 in mitochondrial quality control that involves fine-tuning of CI activity through AS regulation in gastric cancer cells relying highly on mitochondrial respiration.

DOI: https://doi.org/10.1093/narcan/zcad046
Am J Chin Med. 2023 Aug 31. 1-26

Ruscogenin Alleviates Myocardial Ischemia via Myosin IIA-Dependent Mitochondrial Fusion and Fission Balance.

Jin-Cheng Liu, Qing-Fei Zhao, Ling Zhang, Bo-Yang Yu, Fang Li, Jun-Ping Kou.

  Ruscogenin (RUS), a major effective steroidal sapogenin derived from Ophiopogon japonicas, has been reported to alleviate myocardial ischemia (MI), but its cardioprotective mechanism is still not completely clear. In this study, we observed that RUS markedly reduced MI-induced myocardial injury, as evidenced by notable reductions in infarct size, improvement in biochemical markers, alleviation of cardiac pathology, amelioration of mitochondrial damage, and inhibition of myocardial apoptosis. Moreover, RUS notably suppressed oxygen-glucose deprivation (OGD)-triggered cell injury and apoptosis. Notably, RUS demonstrated a considerable decrease of the interaction between myosin IIA and F-actin, along with the restoration of mitochondrial fusion and fission balance. We further confirmed that the effects of RUS on MI were mediated by myosin IIA using siRNA and overexpression techniques. The inhibition of myosin IIA resulted in a significant improvement of mitochondrial fusion and fission imbalance, while simultaneously counteracting the beneficial effects of RUS. By contrast, overexpression of myosin IIA aggravated the imbalance between mitochondrial fusion and fission and partially weakened the protection of RUS. These findings suggest that myosin IIA is essential or even a key functional protein in the cardioprotection of RUS. Overall, our results have elucidated an undiscovered mechanism involving myosin IIA-dependent mitochondrial fusion and fission balance for treating MI. Furthermore, our study has uncovered a novel mechanism underlying the protective effects of RUS.

Keywords:  Apoptosis; Mitochondrial Fission; Mitochondrial Fusion; Myocardial Ischemia; Myosin IIA; Ruscogenin

DOI:  https://doi.org/10.1142/S0192415X23500830
bioRxiv. 2023 Aug 20. pii: 2023.08.20.554022. [Epub ahead of print]

Effects of phosphorylation on Drp1 activation by its receptors, actin, and cardiolipin.

Ao Liu, Anna L Hatch, Henry N Higgs.

Drp1 is a dynamin family GTPase that is required for mitochondrial and peroxisomal division, in which it oligomerizes into a ring and constricts the underlying membrane in a GTP hydrolysis-dependent manner. Oligomerization increases Drp1 GTPase activity through interactions between neighboring GTPase domains. In cells, Drp1 is regulated by several factors including Drp1 receptors, actin filaments, cardiolipin, and phosphorylation at two sites: S579 and S600. Phosphorylation of S579 is widely regarded as activating, while S600 phosphorylation is commonly considered inhibiting. However, the direct effects of phosphorylation on Drp1 GTPase activity have not been investigated in detail. In this study, we compare the effects of S579 and S600 phosphorylation on purified Drp1, using phospho-mimetic mutants and in vitro phosphorylation. The oligomerization state of both phospho-mimetic mutants is shifted toward smaller oligomers. Both phospho-mimetic mutations maintain basal GTPase activity, but eliminate GTPase stimulation by actin and decrease GTPase stimulation by cardiolipin, Mff, and MiD49. Phosphorylation of S579 by Erk2 produces similar effects. When mixed with wild-type Drp1, both S579D and S600D phospho-mimetic mutants reduce the actin-stimulated GTPase activity of Drp1-WT. Conversely, a Drp1 mutant that lacks GTPase activity, the K38A mutant, stimulates Drp1-WT GTPase activity under both basal and actin-stimulated conditions, similar to previous results for dynamin-1. These results suggest that the effect of S579 phosphorylation is not to activate Drp1 directly, and likely requires additional factors for stimulation of mitochondrial fission in cells. In addition, our results suggest that nearest neighbor interactions within the Drp1 oligomer affect catalytic activity.

DOI: https://doi.org/10.1101/2023.08.20.554022
Proc Natl Acad Sci U S A. 2023 Sep 05. 120(36): e2302360120

Impaired age-associated mitochondrial translation is mitigated by exercise and PGC-1α.

Laura M de Smalen, Anastasiya Börsch, Aurel B Leuchtmann, Jonathan F Gill, Danilo Ritz, Mihaela Zavolan, Christoph Handschin.

  Sarcopenia, the age-related loss of skeletal muscle mass and function, can dramatically impinge on quality of life and mortality. While mitochondrial dysfunction and imbalanced proteostasis are recognized as hallmarks of sarcopenia, the regulatory and functional link between these processes is underappreciated and unresolved. We therefore investigated how mitochondrial proteostasis, a crucial process that coordinates the expression of nuclear- and mitochondrial-encoded mitochondrial proteins with supercomplex formation and respiratory activity, is affected in skeletal muscle aging. Intriguingly, a robust mitochondrial translation impairment was observed in sarcopenic muscle, which is regulated by the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α) with the estrogen-related receptor α (ERRα). Exercise, a potent inducer of PGC-1α activity, rectifies age-related reduction in mitochondrial translation, in conjunction with quality control pathways. These results highlight the importance of mitochondrial proteostasis in muscle aging, and elucidate regulatory interactions that underlie the powerful benefits of physical activity in this context.

Keywords:  aging; mitochondria; proteostasis; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1073/pnas.2302360120
Cell Tissue Res. 2023 Aug 29.

The three-dimensional conformation and activity of mitochondria in syncytial male germ line-cysts of medicinal leeches.

Natalia Diak, Małgorzata Alicja Śliwińska, Sebastian Student, Piotr Świątek.

  We studied the spatial conformation and activity of mitochondria in the developing syncytial male germline cysts during spermatogenesis of the medicinal leeches using light, fluorescent, transmission electron microscopy, and serial block-face scanning electron microscopy. In cysts with spermatogonia and spermatocytes, mitochondria form networks and are in a dynamic hyperfusion state, while in cysts with spermatids, a single huge mitochondrion is observed. As spermiogenesis progresses, this huge mitochondrion is finally located in the future midpiece. The highest activity, in terms of membrane potential, of the mitochondria in H. medicinalis germline cysts was observed in cysts with spermatocytes; the lowest was in cysts with late elongated spermatids.

Keywords:  Fission; Fusion; Hirudinidae; Mitochondrial membrane potential; SBEM

DOI:  https://doi.org/10.1007/s00441-023-03825-y
Cartilage. 2023 Aug 30. 19476035231189841

Upregulated Mitochondrial Dynamics Is Responsible for the Procatabolic Changes of Chondrocyte Induced by α2-Adrenergic Signal Activation.

Jiaying He, Wenpin Qin, Yusong Zhang, Jianfei Yan, Xiaoxiao Han, Jialu Gao, Qihong Li, Kai Jiao.

  OBJECTIVE: Activation of sympathetic tone is important for cartilage degradation in osteoarthritis (OA). Recent studies reported that sympathetic signals can affect the mitochondrial function of target cells. It is unknown whether this effect exits in chondrocytes and affects chondrocyte catabolism. The contribution of mitochondrial dynamics in the activation of α2-adrenergic signal-mediated chondrocyte catabolism was investigated in this study.DESIGN: Primary chondrocytes were stimulated with norepinephrine (NE) alone, or pretreated with an α2-adrenergic receptor (Adra2) antagonist (yohimbine) and followed by stimulation with NE. Changes in chondrocyte metabolism and their mitochondrial dynamics were investigated.
RESULTS: We demonstrated that NE stimulation induced increased gene and protein expressions of matrix metalloproteinase-3 and decreased level of aggrecan by chondrocytes. This was accompanied by upregulated mitochondriogenesis and the number of mitochondria, when compared with the vehicle-treated controls. Mitochondrial fusion and fission, and mitophagy also increased significantly in response to NE stimulation. Inhibition of Adra2 attenuated chondrocyte catabolism and mitochondrial dynamics induced by NE.
CONCLUSIONS: The present findings indicate that upregulation of mitochondrial dynamics through mitochondriogenesis, fusion, fission, and mitophagy is responsible for activation of α2-adrenergic signal-mediated chondrocyte catabolism. The hypothesis that "α2-adrenergic signal activation promotes cartilage degeneration in temporomandibular joint osteoarthritis (TMJ-OA) by upregulating mitochondrial dynamics in chondrocytes" is validated. This represents a new regulatory mechanism in the chondrocytes of TMJ-OA that inhibits abnormal activation of mitochondrial fusion and fission is a potential regulator for improving mitochondrial function and inhibiting chondrocyte injury and contrives a potentially innovative therapeutic direction for the prevention of TMJ-OA.

Keywords:  bone biology; degradation; joint disease; matrix metalloproteinases; temporomandibular disorders

DOI:  https://doi.org/10.1177/19476035231189841
Science. 2023 Sep;381(6661): eadg0995

An mTRAN-mRNA interaction mediates mitochondrial translation initiation in plants.

Huy Cuong Tran, Vivian Schmitt, Sbatie Lama, Chuande Wang, Alexandra Launay-Avon, Katja Bernfur, Kristin Sultan, Kasim Khan, Véronique Brunaud, Arnaud Liehrmann, Benoît Castandet, Fredrik Levander, Allan G Rasmusson, Hakim Mireau, Etienne Delannoy, Olivier Van Aken.

Plant mitochondria represent the largest group of respiring organelles on the planet. Plant mitochondrial messenger RNAs (mRNAs) lack Shine-Dalgarno-like ribosome-binding sites, so it is unknown how plant mitoribosomes recognize mRNA. We show that "mitochondrial translation factors" mTRAN1 and mTRAN2 are land plant-specific proteins, required for normal mitochondrial respiration chain biogenesis. Our studies suggest that mTRANs are noncanonical pentatricopeptide repeat (PPR)-like RNA binding proteins of the mitoribosomal "small" subunit. We identified conserved Adenosine (A)/Uridine (U)-rich motifs in the 5' regions of plant mitochondrial mRNAs. mTRAN1 binds this motif, suggesting that it is a mitoribosome homing factor to identify mRNAs. We demonstrate that mTRANs are likely required for translation of all plant mitochondrial mRNAs. Plant mitochondrial translation initiation thus appears to use a protein-mRNA interaction that is divergent from bacteria or mammalian mitochondria.

DOI: https://doi.org/10.1126/science.adg0995
Commun Biol. 2023 08 29. 6(1): 889

Pannexin 1 targets mitophagy to mediate renal ischemia/reperfusion injury.

Lianjiu Su, Jiahao Zhang, Jing Wang, Xiaozhan Wang, Edward Cao, Chen Yang, Qihao Sun, Ramadoss Sivakumar, Zhiyong Peng.

Renal ischemia/reperfusion (I/R) injury contributes to the development of acute kidney injury (AKI). Kidney is the second organ rich in mitochondrial content next to the heart. Mitochondrial damage substantially contributes for AKI development. Mitophagy eliminates damaged mitochondria from the cells to maintain a healthy mitochondrial population, which plays an important role in AKI. Pannexin 1 (PANX1) channel transmembrane proteins are known to drive inflammation and release of adenosine triphosphate (ATP) during I/R injury. However, the specific role of PANX1 on mitophagy regulation in renal I/R injury remains elusive. In this study, we find that serum level of PANX1 is elevated in patients who developed AKI after cardiac surgery, and the level of PANX1 is positively correlated with serum creatinine and urea nitrogen levels. Using the mouse model of renal I/R injury in vivo and cell-based hypoxia/reoxygenation (H/R) model in vitro, we prove that genetic deletion of PANX1 mitigate the kidney tubular cell death, oxidative stress and mitochondrial damage after I/R injury through enhanced mitophagy. Mechanistically, PANX1 disrupts mitophagy by influencing ATP-P2Y-mTOR signal pathway. These observations provide evidence that PANX1 could be a potential biomarker for AKI and a therapeutic target to alleviate AKI caused by I/R injury.

DOI: https://doi.org/10.1038/s42003-023-05226-x
bioRxiv. 2023 Aug 17. pii: 2023.08.16.553624. [Epub ahead of print]

Triaging of ⍺-helical proteins to the mitochondrial outer membrane by distinct chaperone machinery based on substrate topology.

Gayathri Muthukumar, Taylor A Stevens, Alison J Inglis, Theodore K Esantsi, Reuben A Saunders, Fabian Schulte, Rebecca M Voorhees, Alina Guna, Jonathan S Weissman.

Mitochondrial outer membrane ⍺-helical proteins play critical roles in mitochondrial-cytoplasmic communication, but the rules governing the targeting and insertion of these biophysically diverse substrates remain unknown. Here, we first defined the complement of required mammalian biogenesis machinery through genome-wide CRISPRi screens using topologically distinct membrane proteins. Systematic analysis of nine identified factors across 21 diverse ⍺-helical substrates reveals that these components are organized into distinct targeting pathways which act on substrates based on their topology. NAC is required for efficient targeting of polytopic proteins whereas signal-anchored proteins require TTC1, a novel cytosolic chaperone which physically engages substrates. Biochemical and mutational studies reveal that TTC1 employs a conserved TPR domain and a hydrophobic groove in its C-terminal domain to support substrate solubilization and insertion into mitochondria. Thus, targeting of diverse mitochondrial membrane proteins is achieved through topological triaging in the cytosol using principles with similarities to ER membrane protein biogenesis systems.

DOI: https://doi.org/10.1101/2023.08.16.553624
PLoS Biol. 2023 Aug;21(8): e3002246

An interactive deep learning-based approach reveals mitochondrial cristae topologies.

Shogo Suga, Koki Nakamura, Yu Nakanishi, Bruno M Humbel, Hiroki Kawai, Yusuke Hirabayashi.

The convolution of membranes called cristae is a critical structural and functional feature of mitochondria. Crista structure is highly diverse between different cell types, reflecting their role in metabolic adaptation. However, their precise three-dimensional (3D) arrangement requires volumetric analysis of serial electron microscopy and has therefore been limiting for unbiased quantitative assessment. Here, we developed a novel, publicly available, deep learning (DL)-based image analysis platform called Python-based human-in-the-loop workflow (PHILOW) implemented with a human-in-the-loop (HITL) algorithm. Analysis of dense, large, and isotropic volumes of focused ion beam-scanning electron microscopy (FIB-SEM) using PHILOW reveals the complex 3D nanostructure of both inner and outer mitochondrial membranes and provides deep, quantitative, structural features of cristae in a large number of individual mitochondria. This nanometer-scale analysis in micrometer-scale cellular contexts uncovers fundamental parameters of cristae, such as total surface area, orientation, tubular/lamellar cristae ratio, and crista junction density in individual mitochondria. Unbiased clustering analysis of our structural data unraveled a new function for the dynamin-related GTPase Optic Atrophy 1 (OPA1) in regulating the balance between lamellar versus tubular cristae subdomains.

DOI: https://doi.org/10.1371/journal.pbio.3002246
Dev Cell. 2023 Aug 22. pii: S1534-5807(23)00403-3. [Epub ahead of print]

Mechanical stimulation from the surrounding tissue activates mitochondrial energy metabolism in Drosophila differentiating germ cells.

Zong-Heng Wang, Wenjing Zhao, Christian A Combs, Fan Zhang, Jay R Knutson, Mary A Lilly, Hong Xu.

  In multicellular lives, the differentiation of stem cells and progenitor cells is often accompanied by a transition from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). However, the underlying mechanism of this metabolic transition remains largely unknown. In this study, we investigate the role of mechanical stress in activating OXPHOS during differentiation of the female germline cyst in Drosophila. We demonstrate that the surrounding somatic cells flatten the 16-cell differentiating cyst, resulting in an increase of the membrane tension of germ cells inside the cyst. This mechanical stress is necessary to maintain cytosolic Ca2+ concentration in germ cells through a mechanically activated channel, transmembrane channel-like. The sustained cytosolic Ca2+ triggers a CaMKI-Fray-JNK signaling relay, leading to the transcriptional activation of OXPHOS in differentiating cysts. Our findings demonstrate a molecular link between cell mechanics and mitochondrial energy metabolism, with implications for other developmentally orchestrated metabolic transitions in mammals.

Keywords:  CaMKI; Fray; JNK; Myc; TMC; calcium; mechanotransduction; mitochondria; oogenesis; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.devcel.2023.08.007
Biochem Soc Trans. 2023 Aug 29. pii: BST20230012. [Epub ahead of print]

Beyond the TCA cycle: new insights into mitochondrial calcium regulation of oxidative phosphorylation.

Sandra H Lee, Hannah E Duron, Dipayan Chaudhuri.

  While mitochondria oxidative phosphorylation is broadly regulated, the impact of mitochondrial Ca2+ on substrate flux under both physiological and pathological conditions is increasingly being recognized. Under physiologic conditions, mitochondrial Ca2+ enters through the mitochondrial Ca2+ uniporter and boosts ATP production. However, maintaining Ca2+ homeostasis is crucial as too little Ca2+ inhibits adaptation to stress and Ca2+ overload can trigger cell death. In this review, we discuss new insights obtained over the past several years expanding the relationship between mitochondrial Ca2+ and oxidative phosphorylation, with most data obtained from heart, liver, or skeletal muscle. Two new themes are emerging. First, beyond boosting ATP synthesis, Ca2+ appears to be a critical determinant of fuel substrate choice between glucose and fatty acids. Second, Ca2+ exerts local effects on the electron transport chain indirectly, not via traditional allosteric mechanisms. These depend critically on the transporters involved, such as the uniporter or the Na+-Ca2+ exchanger. Alteration of these new relationships during disease can be either compensatory or harmful and suggest that targeting mitochondrial Ca2+ may be of therapeutic benefit during diseases featuring impairments in oxidative phosphorylation.

Keywords:  MCU; NCLX; electron transport chain; mitochondrial dysfunction; mitochondrial permeability transition pores; oxidative phosphorylation

DOI:  https://doi.org/10.1042/BST20230012
iScience. 2023 Sep 15. 26(9): 107539

A dynamic actin cytoskeleton is required to prevent constitutive VDAC-dependent MAPK signalling and aberrant lipid homeostasis.

Jack Davis, Thorsten Meyer, Martin Smolnig, Daniel G J Smethurst, Lisa Neuhaus, Jonas Heyden, Filomena Broeskamp, Elizabeth S M Edrich, Oskar Knittelfelder, Dagmar Kolb, Tobias von der Haar, Campbell W Gourlay, Patrick Rockenfeller.

  The dynamic nature of the actin cytoskeleton is required to coordinate many cellular processes, and a loss of its plasticity has been linked to accelerated cell aging and attenuation of adaptive response mechanisms. Cofilin is an actin-binding protein that controls actin dynamics and has been linked to mitochondrial signaling pathways that control drug resistance and cell death. Here we show that cofilin-driven chronic depolarization of the actin cytoskeleton activates cell wall integrity mitogen-activated protein kinase (MAPK) signalling and disrupts lipid homeostasis in a voltage-dependent anion channel (VDAC)-dependent manner. Expression of the cof1-5 mutation, which reduces the dynamic nature of actin, triggers loss of cell wall integrity, vacuole fragmentation, disruption of lipid homeostasis, lipid droplet (LD) accumulation, and the promotion of cell death. The integrity of the actin cytoskeleton is therefore essential to maintain the fidelity of MAPK signaling, lipid homeostasis, and cell health in S. cerevisiae.

Keywords:  Biological sciences; Cell biology

DOI:  https://doi.org/10.1016/j.isci.2023.107539
Toxicol In Vitro. 2023 Aug 25. pii: S0887-2333(23)00118-2. [Epub ahead of print]93 105669

Curcumin induces mitophagy by promoting mitochondrial succinate dehydrogenase activity and sensitizes human papillary thyroid carcinoma BCPAP cells to radioiodine treatment.

Li Zhang, Ling Qiu, Shichen Xu, Xian Cheng, Jing Wu, Yunping Wang, Wenjing Gao, Jiandong Bao, Huixin Yu.

  Thyroid cancer is one of the most common endocrine malignancies. Differentiated thyroid cancer (DTC) treatment is based on the ability of thyroid follicular cells to accumulate radioactive iodide (RAI). DTC generally has a good prognosis. However, tumor dedifferentiation or defect in certain cell death mechanism occurs in a subset of DTC patients, leading to RAI resistance. Therefore, developing novel therapeutic approaches that enhance RAI sensitivity are still warranted. We found that curcumin, an active ingredient in turmeric with anti-cancer properties, rapidly accumulated in the mitochondria of thyroid cancer cells but not normal epithelial cells. Curcumin treatment triggered mitochondrial membrane depolarization, engulfment of mitochondria within autophagosomes and a robust decrease in mitochondrial mass and proteins, indicating that curcumin selectively induced mitophagy in thyroid cancer cells. In addition, curcumin-induced mitophagic cell death and its synergistic cytotoxic effect with radioiodine could be attenuated by autophagy inhibitor, 3-methyladenine (3-MA). Interestingly, the mechanism of mitophagy-inducing potential of curcumin was its unique mitochondria-targeting property, which induced a burst of SDH activity and excessive ROS production. Our data suggest that curcumin induces mitochondrial dysfunction and triggers lethal mitophagy, which synergizes with radioiodine to kill thyroid cancer cells.

Keywords:  Curcumin; Differentiated thyroid cancer; Mitophagy; Radioactive iodide therapy; Succinate dehydrogenase

DOI:  https://doi.org/10.1016/j.tiv.2023.105669