bims-mikwok 2024-02-11 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024‒02‒11
twenty-one papers selected by
Gavin McStay, Liverpool John Moores University

Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal.
PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX.
Regulation of proteostasis and innate immunity via mitochondria-nuclear communication.
Deficient tRNA posttranscription modification dysregulated the mitochondrial quality controls and apoptosis.
Parkin is a critical player in the effects of caffeine over mitochondrial quality control pathways during skeletal muscle regeneration in mice.
p17/C18-ceramide-mediated mitophagy is an endogenous neuroprotective response in preclinical and clinical brain injury.
MT-TN mutations lead to progressive mitochondrial encephalopathy and promotes mitophagy.
The role of mitochondrial dynamics in oocyte and early embryo development.
Mitochondrial Homeostasis Regulating Mitochondrial Number and Morphology Is a Distinguishing Feature of Skeletal Muscle Fiber Types in Marine Teleosts.
Dual-specificity phosphatase 1 interacts with prohibitin 2 to improve mitochondrial quality control against type-3 cardiorenal syndrome.
The role of DRP1 mediated mitophagy in HT22 cells apoptosis induced by silica nanoparticles.
Precision targeting of CuET overload to disrupt mitochondrial unfolded protein response by integrated liposome.
HTRA2/OMI-Mediated Mitochondrial Quality Control Alters Macrophage Polarization Affecting Systemic Chronic Inflammation.
Mitochondrial stress: a key role of neuroinflammation in stroke.
Mitochondrial Unfolded Protein Response Gene Clpp Is Required for Oocyte Function and Female Fertility.
The role of mitochondrial uncoupling in the regulation of mitostasis after traumatic brain injury.
The human OPA1delTTAG mutation induces adult onset and progressive auditory neuropathy in mice.
Mitochondrial dynamics as a novel treatment strategy for triple-negative breast cancer.
Heat Shock Protein 22 Attenuates Nerve Injury-induced Neuropathic Pain Via Improving Mitochondrial Biogenesis and Reducing Oxidative Stress Mediated By Spinal AMPK/PGC-1α Pathway in Male Rats.
PKM2 induces mitophagy through the AMPK-mTOR pathway promoting CSFV proliferation.
Fluvastatin-induced myofibrillar damage is associated with elevated ROS, and impaired fatty acid oxidation, and is preceded by mitochondrial morphological changes.

Nat Cell Biol. 2024 Feb 08.

Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal.

Laura E Newman, Sammy Weiser Novak, Gladys R Rojas, Nimesha Tadepalle, Cara R Schiavon, Danielle A Grotjahn, Christina G Towers, Marie-Ève Tremblay, Matthew P Donnelly, Sagnika Ghosh, Michaela Medina, Sienna Rocha, Ricardo Rodriguez-Enriquez, Joshua A Chevez, Ian Lemersal, Uri Manor, Gerald S Shadel.

Mitochondrial DNA (mtDNA) encodes essential subunits of the oxidative phosphorylation system, but is also a major damage-associated molecular pattern (DAMP) that engages innate immune sensors when released into the cytoplasm, outside of cells or into circulation. As a DAMP, mtDNA not only contributes to anti-viral resistance, but also causes pathogenic inflammation in many disease contexts. Cells experiencing mtDNA stress caused by depletion of the mtDNA-packaging protein, transcription factor A, mitochondrial (TFAM) or during herpes simplex virus-1 infection exhibit elongated mitochondria, enlargement of nucleoids (mtDNA-protein complexes) and activation of cGAS-STING innate immune signalling via mtDNA released into the cytoplasm. However, the relationship among aberrant mitochondria and nucleoid dynamics, mtDNA release and cGAS-STING activation remains unclear. Here we show that, under a variety of mtDNA replication stress conditions and during herpes simplex virus-1 infection, enlarged nucleoids that remain bound to TFAM exit mitochondria. Enlarged nucleoids arise from mtDNA experiencing replication stress, which causes nucleoid clustering via a block in mitochondrial fission at a stage when endoplasmic reticulum actin polymerization would normally commence, defining a fission checkpoint that ensures mtDNA has completed replication and is competent for segregation into daughter mitochondria. Chronic engagement of this checkpoint results in enlarged nucleoids trafficking into early and then late endosomes for disposal. Endosomal rupture during transit through this endosomal pathway ultimately causes mtDNA-mediated cGAS-STING activation. Thus, we propose that replication-incompetent nucleoids are selectively eliminated by an adaptive mitochondria-endosomal quality control pathway that is prone to innate immune system activation, which might represent a therapeutic target to prevent mtDNA-mediated inflammation during viral infection and other pathogenic states.

DOI: https://doi.org/10.1038/s41556-023-01343-1
bioRxiv. 2024 Jan 25. pii: 2024.01.24.576953. [Epub ahead of print]

PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX.

Lianjie Wei, Mehmet Oguz Gok, Jordyn D Svoboda, Merima Forny, Jonathan R Friedman, Natalie M Niemi.

PPTC7 is a mitochondrial-localized PP2C phosphatase that maintains mitochondrial protein content and metabolic homeostasis. We previously demonstrated that knockout of Pptc7 elevates mitophagy in a BNIP3- and NIX-dependent manner, but the mechanisms by which PPTC7 influences receptor-mediated mitophagy remain ill-defined. Here, we demonstrate that loss of PPTC7 upregulates BNIP3 and NIX post-transcriptionally and independent of HIF-1α stabilization. On a molecular level, loss of PPTC7 prolongs the half-life of BNIP3 and NIX while blunting their accumulation in response to proteasomal inhibition, suggesting that PPTC7 promotes the ubiquitin-mediated turnover of BNIP3 and NIX. Consistently, overexpression of PPTC7 limits the accumulation of BNIP3 and NIX protein levels in response to pseudohypoxia, a well-known inducer of mitophagy. This PPTC7-mediated suppression of BNIP3 and NIX protein expression requires an intact PP2C catalytic motif but is surprisingly independent of its mitochondrial targeting, indicating that PPTC7 influences mitophagy outside of the mitochondrial matrix. We find that PPTC7 exists in at least two distinct states in cells: a longer isoform, which likely represents full length protein, and a shorter isoform, which likely represents an imported, matrix-localized phosphatase pool. Importantly, anchoring PPTC7 to the outer mitochondrial membrane is sufficient to blunt BNIP3 and NIX accumulation, and proximity labeling and fluorescence co-localization experiments suggest that PPTC7 associates with BNIP3 and NIX within the native cellular environment. Importantly, these associations are enhanced in cellular conditions that promote BNIP3 and NIX turnover, demonstrating that PPTC7 is dynamically recruited to BNIP3 and NIX to facilitate their degradation. Collectively, these data reveal that a fraction of PPTC7 dynamically localizes to the outer mitochondrial membrane to promote the proteasomal turnover of BNIP3 and NIX.

DOI: https://doi.org/10.1101/2024.01.24.576953
J Cell Biol. 2024 Mar 04. pii: e202310005. [Epub ahead of print]223(3):

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

Sookyung Kim, Theresa R Ramalho, Cole M Haynes.

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

DOI: https://doi.org/10.1083/jcb.202310005
iScience. 2024 Feb 16. 27(2): 108883

Deficient tRNA posttranscription modification dysregulated the mitochondrial quality controls and apoptosis.

Yunfan He, Gao Zhu, Xincheng Li, Mi Zhou, Min-Xin Guan.

  Mitochondria are dynamic organelles in cellular metabolism and physiology. Mitochondrial DNA (mtDNA) mutations are associated with a broad spectrum of clinical abnormalities. However, mechanisms underlying mtDNA mutations regulate intracellular signaling related to the mitochondrial and cellular integrity are less explored. Here, we demonstrated that mt-tRNAMet 4435A>G mutation-induced nucleotide modification deficiency dysregulated the expression of nuclear genes involved in cytosolic proteins involved in oxidative phosphorylation system (OXPHOS) and impaired the assemble and integrity of OXPHOS complexes. These dysfunctions caused mitochondrial dynamic imbalance, thereby increasing fission and decreasing fusion. Excessive fission impaired the process of autophagy including initiation phase, formation, and maturation of autophagosome. Strikingly, the m.4435A>G mutation upregulated the PARKIN dependent mitophagy pathways but downregulated the ubiquitination-independent mitophagy. These alterations promoted intrinsic apoptotic process for the removal of damaged cells. Our findings provide new insights into mechanism underlying deficient tRNA posttranscription modification regulated intracellular signaling related to the mitochondrial and cellular integrity.

Keywords:  Cell biology; Molecular physiology; Properties of biomolecules

DOI:  https://doi.org/10.1016/j.isci.2024.108883
Acta Physiol (Oxf). 2024 Feb 05. e14111

Parkin is a critical player in the effects of caffeine over mitochondrial quality control pathways during skeletal muscle regeneration in mice.

M V Esteca, I A Divino, A L Vieira da Silva, M B Severino, R R Braga, E R Ropelle, F M Simabuco, I L Baptista.

  AIM: This study aimed to investigate the effects of caffeine on pathways associated with mitochondrial quality control and mitochondrial capacity during skeletal muscle regeneration, focusing on the role of Parkin, a key protein involved in mitophagy.METHODS: We used in vitro C2C12 myoblast during differentiation with and without caffeine in the medium, and we evaluated several markers of mitochondrial quality control pathways and myotube growth. In vivo experiments, we used C57BL/6J (WT) and Parkintm 1Shn lineage (Parkin-/- ) mice and injured tibial anterior muscle. The mice regenerated TA muscle for 3, 10, and 21 days with or without caffeine ingestion. TA muscle was used to analyze the protein content of several markers of mitochondrial quality pathways, muscle satellite cell differentiation, and protein synthesis. Furthermore, it analyzed mtDNA, mitochondrial respiration, and myofiber growth.
RESULTS: C2C12 differentiation experiments showed that caffeine decreased Parkin content, potentially leading to increased DRP1 and PGC-1α content and altered mitochondrial population, thereby enhancing growth capacity. Using Parkin-/- mice, we found that caffeine intake during the regenerative process induces an increase in AMPKα phosphorylation and PGC-1α and TFAM content, changes that were partly Parkin-dependent. In addition, the absence of Parkin potentiates the ergogenic effect of caffeine by increasing mitochondrial capacity and myotube growth. Those effects are related to increased ATF4 content and activation of protein synthesis pathways, such as increased 4E-BP1 phosphorylation.
CONCLUSION: These findings demonstrate that caffeine ingestion changes mitochondrial quality control during skeletal muscle regeneration, and Parkin is a central player in those mechanisms.

Keywords:  AMPK; caffeine; mitochondrial respiration; muscle recovery

DOI:  https://doi.org/10.1111/apha.14111
PNAS Nexus. 2024 Feb;3(2): pgae018

p17/C18-ceramide-mediated mitophagy is an endogenous neuroprotective response in preclinical and clinical brain injury.

Eda Karakaya, Natalia Oleinik, Jazlyn Edwards, Jensen Tomberlin, Randy Bent Barker, Burak Berber, Maria Ericsson, Habeeb Alsudani, Adviye Ergul, Semir Beyaz, John J Lemasters, Besim Ogretmen, Onder Albayram.

Repeat concussions (or repetitive mild traumatic brain injury [rmTBI]) are complex pathological processes consisting of a primary insult and long-term secondary complications and are also a prerequisite for chronic traumatic encephalopathy (CTE). Recent evidence implies a significant role of autophagy-mediated dysfunctional mitochondrial clearance, mitophagy, in the cascade of secondary deleterious events resulting from TBI. C18-ceramide, a bioactive sphingolipid produced in response to cell stress and damage, and its synthesizing enzyme (CerS1) are precursors to selective stress-mediated mitophagy. A transporter, p17, mediates the trafficking of CerS1, induces C18-ceramide synthesis in the mitochondrial membrane, and acts as an elimination signal in cell survival. Whether p17-mediated mitophagy occurs in the brain and plays a causal role in mitochondrial quality control in secondary disease development after rmTBI are unknown. Using a novel repetitive less-than-mild TBI (rlmTBI) injury paradigm, ablation of mitochondrial p17/C18-ceramide trafficking in p17 knockout (KO) mice results in a loss of C18-ceramide-induced mitophagy, which contributes to susceptibility and recovery from long-term secondary complications associated with rlmTBI. Using a ceramide analog with lipid-selenium conjugate drug, LCL768 restored mitophagy and reduced long-term secondary complications, improving cognitive deficits in rlmTBI-induced p17KO mice. We obtained a significant reduction of p17 expression and a considerable decrease of CerS1 and C18-ceramide levels in cortical mitochondria of CTE human brains compared with age-matched control brains. These data demonstrated that p17/C18-ceramide trafficking is an endogenous neuroprotective mitochondrial stress response following rlmTBI, thus suggesting a novel prospective strategy to interrupt the CTE consequences of concussive TBI.

DOI: https://doi.org/10.1093/pnasnexus/pgae018
Biochim Biophys Acta Mol Basis Dis. 2024 Feb 05. pii: S0925-4439(24)00028-0. [Epub ahead of print]1870(4): 167043

MT-TN mutations lead to progressive mitochondrial encephalopathy and promotes mitophagy.

Haolin Duan, Cunhui Pan, Tenghui Wu, Jing Peng, Li Yang.

  Mitochondrial encephalopathy is a neurological disorder caused by impaired mitochondrial function and energy production. One of the genetic causes of this condition is the mutation of MT-TN, a gene that encodes the mitochondrial transfer RNA (tRNA) for asparagine. MT-TN mutations affect the stability and structure of the tRNA, resulting in reduced protein synthesis and complex enzymatic deficiency of the mitochondrial respiratory chain. Our patient cohort manifests with epileptic encephalopathy, ataxia, hypotonia, and bilateral basal ganglia calcification, which differs from previously reported cases. MT-TN mutation deficiency leads to decreased basal and maximal oxygen consumption rates, disrupted spare respiratory capacity, declined mitochondrial membrane potential, and impaired ATP production. Moreover, MT-TN mutations promote mitophagy, a process of selective degradation of damaged mitochondria by autophagy. Excessive mitophagy further leads to mitochondrial biogensis as a compensatory mechanism. In this study, we provided evidence of pathogenicity for two MT-TN mutations, m.5688 T > C and m.G5691A, explored the molecular mechanisms, and summarized the clinical manifestations of MT-TN mutations. Our study expanded the genotype and phenotypic spectrum and provided new insight into mt-tRNA (Asn)-associated mitochondrial encephalopathy.

Keywords:  Epilepsy; MT-TN; Mitochondrial encephalopathy; Mitophagy

DOI:  https://doi.org/10.1016/j.bbadis.2024.167043
Semin Cell Dev Biol. 2024 Feb 06. pii: S1084-9521(24)00019-3. [Epub ahead of print]159-160 52-61

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

Raziye Melike Yildirim, Emre Seli.

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

Keywords:  Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; MtDNA

DOI:  https://doi.org/10.1016/j.semcdb.2024.01.007
Int J Mol Sci. 2024 Jan 26. pii: 1512. [Epub ahead of print]25(3):

Mitochondrial Homeostasis Regulating Mitochondrial Number and Morphology Is a Distinguishing Feature of Skeletal Muscle Fiber Types in Marine Teleosts.

Busu Li, Huan Wang, Xianghui Zeng, Shufang Liu, Zhimeng Zhuang.

  Fishes' skeletal muscles are crucial for swimming and are differentiated into slow-twitch muscles (SM) and fast-twitch muscles (FM) based on physiological and metabolic properties. Consequently, mitochondrial characteristics (number and morphology) adapt to each fiber type's specific functional needs. However, the mechanisms governing mitochondrial adaptation to the specific bioenergetic requirements of each fiber type in teleosts remain unclear. To address this knowledge gap, we investigated the mitochondrial differences and mitochondrial homeostasis status (including biogenesis, autophagy, fission, and fusion) between SM and FM in teleosts using Takifugu rubripes as a representative model. Our findings reveal that SM mitochondria are more numerous and larger compared to FM. To adapt to the increased mitochondrial number and size, SM exhibit elevated mitochondrial biogenesis and dynamics (fission/fusion), yet show no differences in mitochondrial autophagy. Our study provides insights into the adaptive mechanisms shaping mitochondrial characteristics in teleost muscles. The abundance and elongation of mitochondria in SM are maintained through elevated mitochondrial biogenesis, fusion, and fission, suggesting an adaptive response to fulfill the bioenergetic demands of SM that rely extensively on OXPHOS in teleosts. Our findings enhance our understanding of mitochondrial adaptations in diverse muscle types among teleosts and shed light on the evolutionary strategies of bioenergetics in fishes.

Keywords:  Takifugu rubripes; fast-twitch muscles; mitochondrial adaptation; mitochondrial homeostasis; slow-twitch muscles

DOI:  https://doi.org/10.3390/ijms25031512
Int J Med Sci. 2024 ;21(3): 547-561

Dual-specificity phosphatase 1 interacts with prohibitin 2 to improve mitochondrial quality control against type-3 cardiorenal syndrome.

Nanyang Liu, Yanqiu Ding, Hao Zhou, Xing Chang, Long Lou.

  Type-3 cardiorenal syndrome (CRS-3) is acute kidney injury followed by cardiac injury/dysfunction. Mitochondrial injury may impair myocardial function during CRS-3. Since dual-specificity phosphatase 1 (DUSP1) and prohibitin 2 (PHB2) both promote cardiac mitochondrial quality control, we assessed whether these proteins were dysregulated during CRS-3-related cardiac depression. We found that DUSP1 was downregulated in heart tissues from a mouse model of CRS-3. DUSP1 transgenic (DUSP1Tg) mice were protected from CRS-3-induced myocardial damage, as evidenced by their improved heart function and myocardial structure. CRS-3 induced the inflammatory response, oxidative stress and mitochondrial dysfunction in wild-type hearts, but not in DUSP1Tg hearts. DUSP1 overexpression normalized cardiac mitochondrial quality control during CRS-3 by suppressing mitochondrial fission, restoring mitochondrial fusion, re-activating mitophagy and augmenting mitochondrial biogenesis. We found that DUSP1 sustained cardiac mitochondrial quality control by binding directly to PHB2 and maintaining PHB2 phosphorylation, while CRS-3 disrupted this physiological interaction. Transgenic knock-in mice carrying the Phb2S91D variant were less susceptible to cardiac depression upon CRS-3, due to a reduced inflammatory response, suppressed oxidative stress and improved mitochondrial quality control in their heart tissues. Thus, CRS-3-induced myocardial dysfunction can be attributed to reduced DUSP1 expression and disrupted DUSP1/PHB2 binding, leading to defective cardiac mitochondrial quality control.

Keywords:  CRS-3; DUSP1; PHB2; mitochondrial quality control

DOI:  https://doi.org/10.7150/ijms.90484
Ecotoxicol Environ Saf. 2024 Feb 05. pii: S0147-6513(24)00125-8. [Epub ahead of print]272 116050

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

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

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

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

DOI:  https://doi.org/10.1016/j.ecoenv.2024.116050
Int J Biol Macromol. 2024 Feb 06. pii: S0141-8130(24)00777-3. [Epub ahead of print] 129974

Precision targeting of CuET overload to disrupt mitochondrial unfolded protein response by integrated liposome.

Xi Yin, Baojuan Wu, Yaxuan Yang, Jiajun Shi, Yuping Fu, Hongmei Zhang, Jiahui Ye, Yuxiang Sun, Changrong Chen, Yun Zhu, Weijie Zhang.

  Mitochondria in breast cancer play a critical role in survival and adaptation to dynamic environments. Thus, targeting mitochondria emerges as a promising therapeutic strategy for breast cancer. However, the adaptive unfolded protein response in mitochondria (UPRmt) due to mitochondrial unspecific distribution might contribute to diminished therapeutic outcomes. Herein, mitochondrial targeting liposome agents (CTPP-Lipid) are constructed and adopted for delivering the copper ion (CuET-DSF), which is especially sensitive for mitochondria-abundant breast tumors. In brief, the CTPP-Lipid@CuET achieves the goal of Cu2+ overloading by mitochondria targeting delivery. This rapidly increases ROS production, disrupts mitochondrial structure, and avoids the adaptive UPRmt formation, finally leading to apoptosis of breast cancer cells. In general, the Cu2+ overloading at mitochondria by CTPP-Lipid@CuET is a potential strategy for antitumor therapy, providing new insights into breast tumor therapy.

Keywords:  Breast cancer; CTPP; Liposome

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.129974
Int J Mol Sci. 2024 Jan 27. pii: 1577. [Epub ahead of print]25(3):

HTRA2/OMI-Mediated Mitochondrial Quality Control Alters Macrophage Polarization Affecting Systemic Chronic Inflammation.

Qingqing Liu, Xiaoyu Yan, Yuan Yuan, Runyuan Li, Yuanxin Zhao, Jiaying Fu, Jian Wang, Jing Su.

  Systemic chronic inflammation (SCI) due to intrinsic immune over-activation is an important factor in the development of many noninfectious chronic diseases, such as neurodegenerative diseases and diabetes mellitus. Among these immune responses, macrophages are extensively involved in the regulation of inflammatory responses by virtue of their polarization plasticity; thus, dysregulation of macrophage polarization direction is one of the potential causes of the generation and maintenance of SCI. High-temperature demand protein A2 (HtrA2/Omi) is an important regulator of mitochondrial quality control, not only participating in the degradation of mis-accumulated proteins in the mitochondrial unfolded protein response (UPRmt) to maintain normal mitochondrial function through its enzymatic activity, but also participating in the regulation of mitochondrial dynamics-related protein interactions to maintain mitochondrial morphology. Recent studies have also reported the involvement of HtrA2/Omi as a novel inflammatory mediator in the regulation of the inflammatory response. HtrA2/Omi regulates the inflammatory response in BMDM by controlling TRAF2 stabilization in a collagen-induced arthritis mouse model; the lack of HtrA2 ameliorates pro-inflammatory cytokine expression in macrophages. In this review, we summarize the mechanisms by which HtrA2/Omi proteins are involved in macrophage polarization remodeling by influencing macrophage energy metabolism reprogramming through the regulation of inflammatory signaling pathways and mitochondrial quality control, elucidating the roles played by HtrA2/Omi proteins in inflammatory responses. In conclusion, interfering with HtrA2/Omi may become an important entry point for regulating macrophage polarization, providing new research space for developing HtrA2/Omi-based therapies for SCI.

Keywords:  HtrA2/Omi; SCI; inflammation; macrophages; mitochondria

DOI:  https://doi.org/10.3390/ijms25031577
J Neuroinflammation. 2024 Feb 06. 21(1): 44

Mitochondrial stress: a key role of neuroinflammation in stroke.

Ling Gao, Li Peng, Jian Wang, John H Zhang, Ying Xia.

  Stroke is a clinical syndrome characterized by an acute, focal neurological deficit, primarily caused by the occlusion or rupture of cerebral blood vessels. In stroke, neuroinflammation emerges as a pivotal event contributing to neuronal cell death. The occurrence and progression of neuroinflammation entail intricate processes, prominently featuring mitochondrial dysfunction and adaptive responses. Mitochondria, a double membrane-bound organelle are recognized as the "energy workshop" of the body. Brain is particularly vulnerable to mitochondrial disturbances due to its high energy demands from mitochondria-related energy production. The interplay between mitochondria and neuroinflammation plays a significant role in the pathogenesis of stroke. The biological and pathological consequences resulting from mitochondrial stress have substantial implications for cerebral function. Mitochondrial stress serves as an adaptive mechanism aimed at mitigating the stress induced by the import of misfolded proteins, which occurs in response to stroke. This adaptive response involves a reduction in misfolded protein accumulation and overall protein synthesis. The influence of mitochondrial stress on the pathological state of stroke is underscored by its capacity to interact with neuroinflammation. The impact of mitochondrial stress on neuroinflammation varies according to its severity. Moderate mitochondrial stress can bolster cellular adaptive defenses, enabling cells to better withstand detrimental stressors. In contrast, sustained and excessive mitochondrial stress detrimentally affects cellular and tissue integrity. The relationship between neuroinflammation and mitochondrial stress depends on the degree of mitochondrial stress present. Understanding its role in stroke pathogenesis is instrumental in excavating the novel treatment of stroke. This review aims to provide the evaluation of the cross-talk between mitochondrial stress and neuroinflammation within the context of stroke. We aim to reveal how mitochondrial stress affects neuroinflammation environment in stroke.

Keywords:  Mitochondrial stress; Mitophagy; Neuroinflammation; Stroke

DOI:  https://doi.org/10.1186/s12974-024-03033-7
Int J Mol Sci. 2024 Feb 03. pii: 1866. [Epub ahead of print]25(3):

Mitochondrial Unfolded Protein Response Gene Clpp Is Required for Oocyte Function and Female Fertility.

Yagmur Ergun, Aysegul Gizem Imamoglu, Mauro Cozzolino, Cem Demirkiran, Murat Basar, Akanksha Garg, Raziye Melike Yildirim, Emre Seli.

  Mitochondrial unfolded protein stress response (mtUPR) plays a critical role in regulating cellular and metabolic stress response and helps maintain protein homeostasis. Caseinolytic peptidase P (CLPP) is one of the key regulators of mtUPR and promotes unfolded protein degradation. Previous studies demonstrated that global deletion of Clpp resulted in female infertility, whereas no impairment was found in the mouse model with targeted deletion of Clpp in cumulus/granulosa cells. These results suggest the need to delineate the function of Clpp in oocytes. In this study, we aimed to further explore the role of mtUPR in female reproductive competence and senescence using a mouse model. Oocyte-specific targeted deletion of Clpp in mice resulted in female subfertility associated with metabolic and functional abnormalities in oocytes, thus highlighting the importance of CLPP-mediated protein homeostasis in oocyte competence and reproductive function.

Keywords:  CLPP; female fertility; mitochondrial dysfunction; mitochondrial stress response; oocyte function

DOI:  https://doi.org/10.3390/ijms25031866
Neurochem Int. 2024 Feb 02. pii: S0197-0186(24)00007-X. [Epub ahead of print] 105680

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

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

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

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

DOI:  https://doi.org/10.1016/j.neuint.2024.105680
Cell Mol Life Sci. 2024 Feb 09. 81(1): 80

The human OPA1delTTAG mutation induces adult onset and progressive auditory neuropathy in mice.

Corentin Affortit, Carolanne Coyat, Anissa Rym Saidia, Jean-Charles Ceccato, Majida Charif, Emmanuelle Sarzi, Frédéric Flamant, Romain Guyot, Chantal Cazevieille, Jean-Luc Puel, Guy Lenaers, Jing Wang.

  Dominant optic atrophy (DOA) is one of the most prevalent forms of hereditary optic neuropathies and is mainly caused by heterozygous variants in OPA1, encoding a mitochondrial dynamin-related large GTPase. The clinical spectrum of DOA has been extended to a wide variety of syndromic presentations, called DOAplus, including deafness as the main secondary symptom associated to vision impairment. To date, the pathophysiological mechanisms underlying the deafness in DOA remain unknown. To gain insights into the process leading to hearing impairment, we have analyzed the Opa1delTTAG mouse model that recapitulates the DOAplus syndrome through complementary approaches combining morpho-physiology, biochemistry, and cellular and molecular biology. We found that Opa1delTTAG mutation leads an adult-onset progressive auditory neuropathy in mice, as attested by the auditory brainstem response threshold shift over time. However, the mutant mice harbored larger otoacoustic emissions in comparison to wild-type littermates, whereas the endocochlear potential, which is a proxy for the functional state of the stria vascularis, was comparable between both genotypes. Ultrastructural examination of the mutant mice revealed a selective loss of sensory inner hair cells, together with a progressive degeneration of the axons and myelin sheaths of the afferent terminals of the spiral ganglion neurons, supporting an auditory neuropathy spectrum disorder (ANSD). Molecular assessment of cochlea demonstrated a reduction of Opa1 mRNA level by greater than 40%, supporting haploinsufficiency as the disease mechanism. In addition, we evidenced an early increase in Sirtuin 3 level and in Beclin1 activity, and subsequently an age-related mtDNA depletion, increased oxidative stress, mitophagy as well as an impaired autophagic flux. Together, these results support a novel role for OPA1 in the maintenance of inner hair cells and auditory neural structures, addressing new challenges for the exploration and treatment of OPA1-linked ANSD in patients.

Keywords:  Deafness; Hereditary optic neuropathy; Hidden hearing loss; Inner ear; Inner hair cell; Mitochondrial homeostasis; Outer hair cell; Retina

DOI:  https://doi.org/10.1007/s00018-024-05115-4
Cancer Med. 2024 Jan;13(2): e6987

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

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

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

Keywords:  breast cancer; drug resistance; mitochondria; mitophagy

DOI:  https://doi.org/10.1002/cam4.6987
J Neuroimmune Pharmacol. 2024 Feb 06. 19(1): 5

Heat Shock Protein 22 Attenuates Nerve Injury-induced Neuropathic Pain Via Improving Mitochondrial Biogenesis and Reducing Oxidative Stress Mediated By Spinal AMPK/PGC-1α Pathway in Male Rats.

Longqing Zhang, Lin Liu, Danyang Li, Jiayi Wu, Shaojie Gao, Fanhe Song, Yaqun Zhou, Daiqiang Liu, Wei Mei.

  Heat shock protein 22 (hsp22) plays a significant role in mitochondrial biogenesis and redox balance. Moreover, it's well accepted that the impairment of mitochondrial biogenesis and redox imbalance contributes to the progress of neuropathic pain. However, there is no available evidence indicating that hsp22 can ameliorate mechanical allodynia and thermal hyperalgesia, sustain mitochondrial biogenesis and redox balance in rats with neuropathic pain. In this study, pain behavioral test, western blotting, immunofluorescence staining, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and Dihydroethidium staining are applied to confirm the role of hsp22 in a male rat model of spared nerve injury (SNI). Our results indicate that hsp22 was significantly decreased in spinal neurons post SNI. Moreover, it was found that intrathecal injection (i.t.) with recombinant heat shock protein 22 protein (rhsp22) ameliorated mechanical allodynia and thermal hyperalgesia, facilitated nuclear respiratory factor 1 (NRF1)/ mitochondrial transcription factor A (TFAM)-dependent mitochondrial biogenesis, decreased the level of reactive oxygen species (ROS), and suppressed oxidative stress via activation of spinal adenosine 5'monophosphate-activated protein kinase (AMPK)/ peroxisome proliferative activated receptor γ coactivator 1α (PGC-1α) pathway in male rats with SNI. Furthermore, it was also demonstrated that AMPK antagonist (compound C, CC) or PGC-1α siRNA reversed the improved mechanical allodynia and thermal hyperalgesia, mitochondrial biogenesis, oxidative stress, and the decreased ROS induced by rhsp22 in male rats with SNI. These results revealed that hsp22 alleviated mechanical allodynia and thermal hyperalgesia, improved the impairment of NRF1/TFAM-dependent mitochondrial biogenesis, down-regulated the level of ROS, and mitigated oxidative stress through stimulating the spinal AMPK/PGC-1α pathway in male rats with SNI.

Keywords:  Mitochondrial biogenesis; Mitochondrial dysfunction; Neuropathic pain; Oxidative stress; ROS; hsp22

DOI:  https://doi.org/10.1007/s11481-024-10100-6
J Virol. 2024 Feb 06. e0175123

PKM2 induces mitophagy through the AMPK-mTOR pathway promoting CSFV proliferation.

Xiaodi Liu, Quanhui Yan, Xueyi Liu, Wenkang Wei, Linke Zou, Feifan Zhao, Sen Zeng, Lin Yi, Hongxing Ding, Mingqiu Zhao, Jinding Chen, Shuangqi Fan.

  Viruses exploit the host cell's energy metabolism system to support their replication. Mitochondria, known as the powerhouse of the cell, play a critical role in regulating cell survival and virus replication. Our prior research indicated that the classical swine fever virus (CSFV) alters mitochondrial dynamics and triggers glycolytic metabolic reprogramming. However, the role and mechanism of PKM2, a key regulatory enzyme of glycolytic metabolism, in CSFV replication remain unclear. In this study, we discovered that CSFV enhances PKM2 expression and utilizes PKM2 to inhibit pyruvate production. Using an affinity purification coupled mass spectrometry system, we successfully identified PKM as a novel interaction partner of the CSFV non-structural protein NS4A. Furthermore, we validated the interaction between PKM2 and both CSFV NS4A and NS5A through co-immunoprecipitation and confocal analysis. PKM2 was found to promote the expression of both NS4A and NS5A. Moreover, we observed that PKM2 induces mitophagy by activating the AMPK-mTOR signaling pathway, thereby facilitating CSFV proliferation. In summary, our data reveal a novel mechanism whereby PKM2, a metabolic enzyme, promotes CSFV proliferation by inducing mitophagy. These findings offer a new avenue for developing antiviral strategies.IMPORTANCEViruses rely on the host cell's material-energy metabolic system for replication, inducing host metabolic disorders and subsequent immunosuppression-a major contributor to persistent viral infections. Classical swine fever virus (CSFV) is no exception. Classical swine fever is a severe acute infectious disease caused by CSFV, resulting in significant economic losses to the global pig industry. While the role of the metabolic enzyme PKM2 (pyruvate dehydrogenase) in the glycolytic pathway of tumor cells has been extensively studied, its involvement in viral infection remains relatively unknown. Our data unveil a new mechanism by which the metabolic enzyme PKM2 mediates CSFV infection, offering novel avenues for the development of antiviral strategies.

Keywords:  AMPK-mTOR; cellular metabolism; classical swine fever virus; mitophagy; pyruvate kinase M2; viral infection

DOI:  https://doi.org/10.1128/jvi.01751-23
Sci Rep. 2024 Feb 09. 14(1): 3338

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

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

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

DOI: https://doi.org/10.1038/s41598-024-53446-w