bims-minimp 2022-06-26 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2022‒06‒26
ten papers selected by
Hanna Salmonowicz
International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

Chronic inhibition of the mitochondrial ATP synthase in skeletal muscle triggers sarcoplasmic reticulum distress and tubular aggregates.
Most mitochondrial dGTP is tightly bound to respiratory complex I through the NDUFA10 subunit.
Shaping fuel utilization by mitochondria.
TFAM downregulation promotes autophagy and ESCC survival through mtDNA stress-mediated STING pathway.
Mitochondrial-derived vesicles: Gatekeepers of mitochondrial response to oxidative stress.
Structural basis of Tom20 and Tom22 cytosolic domains as the human TOM complex receptors.
PGC-1α-Mediated Mitochondrial Quality Control: Molecular Mechanisms and Implications for Heart Failure.
Doxorubicin-induced senescence in normal fibroblasts promotes in vitro tumour cell growth and invasiveness: the role of Quercetin in modulating these processes.
The decylTPP mitochondria-targeting moiety lowers electron transport chain supercomplex levels in primary human skin fibroblasts.
TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia.

Cell Death Dis. 2022 Jun 22. 13(6): 561

Chronic inhibition of the mitochondrial ATP synthase in skeletal muscle triggers sarcoplasmic reticulum distress and tubular aggregates.

Cristina Sánchez-González, Juan Cruz Herrero Martín, Beñat Salegi Ansa, Cristina Núñez de Arenas, Brina Stančič, Marta P Pereira, Laura Contreras, José M Cuezva, Laura Formentini.

Tubular aggregates (TA) are honeycomb-like arrays of sarcoplasmic-reticulum (SR) tubules affecting aged glycolytic fibers of male individuals and inducing severe sarcomere disorganization and muscular pain. TA develop in skeletal muscle from Tubular Aggregate Myopathy (TAM) patients as well as in other disorders including endocrine syndromes, diabetes, and ageing, being their primary cause unknown. Nowadays, there is no cure for TA. Intriguingly, both hypoxia and calcium dyshomeostasis prompt TA formation, pointing to a possible role for mitochondria in their setting. However, a functional link between mitochondrial dysfunctions and TA remains unknown. Herein, we investigate the alteration in muscle-proteome of TAM patients, the molecular mechanism of TA onset and a potential therapy in a preclinical mouse model of the disease. We show that in vivo chronic inhibition of the mitochondrial ATP synthase in muscle causes TA. Upon long-term restrained oxidative phosphorylation (OXPHOS), oxidative soleus experiments a metabolic and structural switch towards glycolytic fibers, increases mitochondrial fission, and activates mitophagy to recycle damaged mitochondria. TA result from the overresponse of the fission controller DRP1, that upregulates the Store-Operate-Calcium-Entry and increases the mitochondria-SR interaction in a futile attempt to buffer calcium overloads upon prolonged OXPHOS inhibition. Accordingly, hypoxic muscles cultured ex vivo show an increase in mitochondria/SR contact sites and autophagic/mitophagic zones, where TA clusters grow around defective mitochondria. Moreover, hypoxia triggered a stronger TA formation upon ATP synthase inhibition, and this effect was reduced by the DRP1 inhibitor mDIVI. Remarkably, the muscle proteome of TAM patients displays similar alterations in mitochondrial dynamics and in ATP synthase contents. In vivo edaravone treatment in mice with restrained OXPHOS restored a healthy phenotype by prompting mitogenesis and mitochondrial fusion. Altogether, our data provide a functional link between the ATP synthase/DRP1 axis and the setting of TA, and repurpose edaravone as a possible treatment for TA-associated disorders.

DOI: https://doi.org/10.1038/s41419-022-05016-z
Commun Biol. 2022 Jun 23. 5(1): 620

Most mitochondrial dGTP is tightly bound to respiratory complex I through the NDUFA10 subunit.

David Molina-Granada, Emiliano González-Vioque, Marris G Dibley, Raquel Cabrera-Pérez, Antoni Vallbona-Garcia, Javier Torres-Torronteras, Leonid A Sazanov, Michael T Ryan, Yolanda Cámara, Ramon Martí.

Imbalanced mitochondrial dNTP pools are known players in the pathogenesis of multiple human diseases. Here we show that, even under physiological conditions, dGTP is largely overrepresented among other dNTPs in mitochondria of mouse tissues and human cultured cells. In addition, a vast majority of mitochondrial dGTP is tightly bound to NDUFA10, an accessory subunit of complex I of the mitochondrial respiratory chain. NDUFA10 shares a deoxyribonucleoside kinase (dNK) domain with deoxyribonucleoside kinases in the nucleotide salvage pathway, though no specific function beyond stabilizing the complex I holoenzyme has been described for this subunit. We mutated the dNK domain of NDUFA10 in human HEK-293T cells while preserving complex I assembly and activity. The NDUFA10E160A/R161A shows reduced dGTP binding capacity in vitro and leads to a 50% reduction in mitochondrial dGTP content, proving that most dGTP is directly bound to the dNK domain of NDUFA10. This interaction may represent a hitherto unknown mechanism regulating mitochondrial dNTP availability and linking oxidative metabolism to DNA maintenance.

DOI: https://doi.org/10.1038/s42003-022-03568-6
Curr Biol. 2022 Jun 20. pii: S0960-9822(22)00765-5. [Epub ahead of print]32(12): R618-R623

Shaping fuel utilization by mitochondria.

Lukas Alan, Luca Scorrano.

Mitochondria are central to cellular metabolism. They provide intermediate metabolites that are used in biosynthetic pathways and they process diet-derived nutrients into the energy-rich compound ATP. Mitochondrial ATP biosynthesis is a marvel of thermodynamic efficiency. Via the tricarboxylic acid cycle (TCA) and fatty acid β-oxidation, mitochondria extract electrons from dietary carbon compounds and pass them to nucleotides that ultimately deliver them to the respiratory chain complexes located in invaginations in the inner mitochondrial membrane (IMM) known as cristae. The respiratory chain complexes donate electrons in stepwise redox reactions to molecular oxygen and, with the exception of complex II, use the liberated energy to pump protons across the proton-impermeable IMM, generating a proton electrochemical gradient. This gradient is then utilized by the ATP synthase, which, in a rotary mechanism, catalyzes the formation of the high-energy γ-phosphate chemical bond between ADP and inorganic phosphate. The conversion of the chemical energy of carbon compounds into a physical, vectorial form of energy (the electrochemical gradient) maximizes the yield of the ATP biosynthetic process and is perhaps one of the foundations of life as we know it.

DOI: https://doi.org/10.1016/j.cub.2022.05.006
Oncogene. 2022 Jun 24.

TFAM downregulation promotes autophagy and ESCC survival through mtDNA stress-mediated STING pathway.

Yujia Li, Qi Yang, Hui Chen, Xiaotian Yang, Jingru Han, Xiaojuan Yao, Xiajie Wei, Jiaoyang Si, Huanling Yao, Hongliang Liu, Lixin Wan, Hushan Yang, Yanming Wang, Dengke Bao.

The dynamics of mitochondrial biogenesis regulation is critical in maintaining cellular homeostasis for immune regulation and tumor prevention. Here, we report that mitochondrial biogenesis disruption through TFAM reduction significantly impairs mitochondrial function, induces autophagy, and promotes esophageal squamous cell carcinoma (ESCC) growth. We found that TFAM protein reduction promotes mitochondrial DNA (mtDNA) release into the cytosol, induces cytosolic mtDNA stress, subsequently activates the cGAS-STING signaling pathway, thereby stimulating autophagy and ESCC growth. STING depletion or mtDNA degradation by DNase I abrogates mtDNA stress response, attenuates autophagy, and decreases the growth of TFAM depleted cells. In addition, autophagy inhibitor also ameliorates mitochondrial dysfunction-induced activation of the cGAS-STING signaling pathway and ESCC growth. In conclusion, our results indicate that mtDNA stress induced by mitochondria biogenesis perturbation activates the cGAS-STING pathway and autophagy to promote ESCC growth, revealing an underappreciated therapeutic strategy for ESCC.

DOI: https://doi.org/10.1038/s41388-022-02365-z
Free Radic Biol Med. 2022 Jun 21. pii: S0891-5849(22)00460-9. [Epub ahead of print]

Mitochondrial-derived vesicles: Gatekeepers of mitochondrial response to oxidative stress.

Tingting Peng, Yinyin Xie, Hanqing Sheng, Cui Wang, Yajun Lian, Nanchang Xie.

  Mitochondrial quality control (MQC) mechanisms are a series of adaptive responses that ensure the relative stability of mitochondrial morphology, quantity, and quality to preserve cellular survival and function. While MQC mechanisms range from mitochondrial biogenesis and fusion/fission to mitophagy, mitochondrial-derived vesicles (MDVs) may represent an essential component of MQC. MDVs precede mitochondrial autophagy and serve as the first line of defense against oxidative stress by selectively transferring damaged mitochondrial substances to the lysosome for degradation. In fact, the function of MDVs is dependent on the cargo, the shuttle route, and the ultimate destination. Abnormal MDVs disrupt metabolite clearance and the immune response, predisposing to pathological conditions, including neurodegeneration, cardiovascular diseases, and cancers. Therefore, MDV regulation may be a potential therapeutic for the therapy of these diseases. In this review, we highlight recent advances in the study of MDVs and their misregulation in various diseases from the perspectives of formation, cargo selection, regulation, and transportation.

Keywords:  Aging; Diseases; Mitochondria; Mitochondrial quality control; Mitochondrial-derived vesicle; Therapeutics

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.06.233
Proc Natl Acad Sci U S A. 2022 Jun 28. 119(26): e2200158119

Structural basis of Tom20 and Tom22 cytosolic domains as the human TOM complex receptors.

Jiayue Su, Desheng Liu, Fan Yang, Mei-Qing Zuo, Chang Li, Meng-Qiu Dong, Shan Sun, Sen-Fang Sui.

  Mitochondrial preproteins synthesized in cytosol are imported into mitochondria by a multisubunit translocase of the outer membrane (TOM) complex. Functioned as the receptor, the TOM complex components, Tom 20, Tom22, and Tom70, recognize the presequence and further guide the protein translocation. Their deficiency has been linked with neurodegenerative diseases and cardiac pathology. Although several structures of the TOM complex have been reported by cryoelectron microscopy (cryo-EM), how Tom22 and Tom20 function as TOM receptors remains elusive. Here we determined the structure of TOM core complex at 2.53 Å and captured the structure of the TOM complex containing Tom22 and Tom20 cytosolic domains at 3.74 Å. Structural analysis indicates that Tom20 and Tom22 share a similar three-helix bundle structural feature in the cytosolic domain. Further structure-guided biochemical analysis reveals that the Tom22 cytosolic domain is responsible for binding to the presequence, and the helix H1 is critical for this binding. Altogether, our results provide insights into the functional mechanism of the TOM complex recognizing and transferring preproteins across the mitochondrial membrane.

Keywords:  TOM complex; Tom20; Tom22; cryo-EM; mitochondria

DOI:  https://doi.org/10.1073/pnas.2200158119
Front Cell Dev Biol. 2022 ;10 871357

PGC-1α-Mediated Mitochondrial Quality Control: Molecular Mechanisms and Implications for Heart Failure.

Lei Chen, Yuan Qin, Bilin Liu, Meng Gao, Anqi Li, Xue Li, Guohua Gong.

  Mitochondria with structural and functional integrity are essential for maintaining mitochondrial function and cardiac homeostasis. It is involved in the pathogenesis of many diseases. Peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α), acted as a transcriptional cofactor, is abundant in the heart, which modulates mitochondrial biogenesis and mitochondrial dynamics and mitophagy to sustain a steady-state of mitochondria. Cumulative evidence suggests that dysregulation of PGC-1α is closely related to the onset and progression of heart failure. PGC-1α deficient-mice can lead to worse cardiac function under pressure overload compared to sham. Here, this review mainly focuses on what is known about its regulation in mitochondrial functions, as well as its crucial role in heart failure.

Keywords:  PGC-1α; heart failure; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial quality control

DOI:  https://doi.org/10.3389/fcell.2022.871357
Mech Ageing Dev. 2022 Jun 18. pii: S0047-6374(22)00071-9. [Epub ahead of print] 111689

Doxorubicin-induced senescence in normal fibroblasts promotes in vitro tumour cell growth and invasiveness: the role of Quercetin in modulating these processes.

Elisa Bientinesi, Matteo Lulli, Matteo Becatti, Sara Ristori, Francesca Margheri, Daniela Monti.

  Ageing is a complex biological phenomenon representing the major risk factor for developing age-related diseases, such as cardiovascular pathologies, neurodegenerative diseases, and cancer. Geroscience, the new vision of gerontology, identifies cellular senescence as an interconnected biological process that characterises ageing and age-related diseases. Therefore, many strategies have been employed in the last years to reduce the harmful effects of senescence, and among these, the most intriguing ones use nutraceutical compounds. Here we show that a pre-treatment with Quercetin, a bioactive flavonoid present in many fruits and vegetables, increasing cellular antioxidant defence, can alleviate Doxorubicin (Doxo)-induced cellular senescence in human normal WI-38 fibroblasts. Furthermore, our work demonstrates that Quercetin pre-treatment, reducing the number of senescent cells and the production of the senescence-associated secretory phenotype (SASP) factors, can decrease the pro-tumour effects of conditioned medium from Doxo-induced senescent fibroblasts on osteosarcoma cells. Overall, our findings are consistent with the hypothesis that targeting senescent cells can be an emerging strategy for cancer treatment, especially in elderly patients, in which senescent cells are already abundant in several tissues and organs.

Keywords:  Ageing; Cancer; Osteosarcoma; Quercetin; SASP; Senescence

DOI:  https://doi.org/10.1016/j.mad.2022.111689
Free Radic Biol Med. 2022 Jun 16. pii: S0891-5849(22)00238-6. [Epub ahead of print]

The decylTPP mitochondria-targeting moiety lowers electron transport chain supercomplex levels in primary human skin fibroblasts.

Elianne P Bulthuis, Claudia Einer, Felix Distelmaier, Laszlo Groh, Sjenet E van Emst-de Vries, Els van de Westerlo, Melissa van de Wal, Jori Wagenaars, Richard J Rodenburg, Jan A M Smeitink, Niels P Riksen, Peter H G M Willems, Merel J W Adjobo-Hermans, Hans Zischka, Werner J H Koopman.

  Attachment of cargo molecules to lipophilic triphenylphosphonium (TPP+) cations is a widely applied strategy for mitochondrial targeting. We previously demonstrated that the vitamin E-derived antioxidant Trolox increases the levels of active mitochondrial complex I (CI), the first complex of the electron transport chain (ETC), in primary human skin fibroblasts (PHSFs) of Leigh Syndrome (LS) patients with isolated CI deficiency. Primed by this finding, we here studied the cellular effects of mitochondria-targeted Trolox (MitoE10), mitochondria-targeted ubiquinone (MitoQ10) and their mitochondria-targeting moiety decylTPP (C10-TPP+). Chronic treatment (96 h) with these molecules of PHSFs from a healthy subject and an LS patient with isolated CI deficiency (NDUFS7-V122 M mutation) did not greatly affect cell number. Unexpectedly, this treatment reduced CI levels/activity, lowered the amount of ETC supercomplexes, inhibited mitochondrial oxygen consumption, increased extracellular acidification, altered mitochondrial morphology and stimulated hydroethidine oxidation. We conclude that the mitochondria-targeting decylTPP moiety is responsible for the observed effects and advocate that every study employing alkylTPP-mediated mitochondrial targeting should routinely include control experiments with the corresponding alkylTPP moiety.

Keywords:  Complex I; Glycolysis; Mitochondrial targeting; Supercomplexes; Trolox; decylTPP

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.06.011
Brain. 2022 Jun 20. pii: awac123. [Epub ahead of print]

TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia.

Luis Carlos Tábara, Fatema Al-Salmi, Reza Maroofian, Amna Mohammed Al-Futaisi, Fathiya Al-Murshedi, Joanna Kennedy, Jacob O Day, Thomas Courtin, Aisha Al-Khayat, Hamid Galedari, Neda Mazaheri, Margherita Protasoni, Mark Johnson, Joseph S Leslie, Claire G Salter, Lettie E Rawlins, James Fasham, Almundher Al-Maawali, Nikol Voutsina, Perrine Charles, Laura Harrold, Boris Keren, Edmund R S Kunji, Barbara Vona, Gholamreza Jelodar, Alireza Sedaghat, Gholamreza Shariati, Henry Houlden, Andrew H Crosby, Julien Prudent, Emma L Baple.

  The hereditary spastic paraplegias (HSP) are among the most genetically diverse of all Mendelian disorders. They comprise a large group of neurodegenerative diseases that may be divided into 'pure HSP' in forms of the disease primarily entailing progressive lower-limb weakness and spasticity, and 'complex HSP' when these features are accompanied by other neurological (or non-neurological) clinical signs. Here, we identified biallelic variants in the transmembrane protein 63C (TMEM63C) gene, encoding a predicted osmosensitive calcium-permeable cation channel, in individuals with hereditary spastic paraplegias associated with mild intellectual disability in some, but not all cases. Biochemical and microscopy analyses revealed that TMEM63C is an endoplasmic reticulum-localized protein, which is particularly enriched at mitochondria-endoplasmic reticulum contact sites. Functional in cellula studies indicate a role for TMEM63C in regulating both endoplasmic reticulum and mitochondrial morphologies. Together, these findings identify autosomal recessive TMEM63C variants as a cause of pure and complex HSP and add to the growing evidence of a fundamental pathomolecular role of perturbed mitochondrial-endoplasmic reticulum dynamics in motor neurone degenerative diseases.

Keywords:  TMEM63C; endoplasmic reticulum/ER; hereditary spastic paraplegia/HSP; mitochondria; mitochondria-ER contact sites/MERCs

DOI:  https://doi.org/10.1093/brain/awac123