bims-tofagi 2023-12-24 papers

on Mitophagy

Issue of 2023‒12‒24
nine papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea

Generation of inducible mitophagy mice.
Mitochondrial quality control pathways sense mitochondrial protein import.
Mitochondrial quality control via organelle and protein degradation.
FBXL4 mutation-caused mitochondrial DNA depletion syndrome is driven by BNIP3/BNIP3L-dependent excessive mitophagy.
Quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging process.
Disruption of Mitophagy Flux through the PARL-PINK1 Pathway by CHCHD10 Mutations or CHCHD10 Depletion.
Fingolimod exerts neuroprotection by regulating S1PR1 mediated BNIP3-PINK1-Parkin dependent mitophagy in rotenone induced mouse model of Parkinson's disease.
The role of mitochondrial quality control in chronic obstructive pulmonary disease.
A novel mechanism of PHB2-mediated mitophagy participating in the development of Parkinson's disease.

Genes Cells. 2023 Dec 22.

Generation of inducible mitophagy mice.

Toshiyuki Nishiji, Atsushi Hoshino, Yuki Uchio, Satoaki Matoba.

  Mitophagy is programmed selective autophagy of mitochondria and is important for mitochondrial quality control and cellular homeostasis. Mitochondrial dysfunction and impaired mitophagy are closely associated with various diseases, including heart failure and diabetes. To better understand the pathophysiological role of mitophagy, we generated doxycycline-inducible mitophagy mice using a synthetic mitophagy adaptor protein consisting of an outer mitochondrial membrane targeting sequence and an engineered LIR. To evaluate the activation of mitophagy upon doxycycline treatment, we also generated mitophagy reporter mito-QC mice in which mitochondria tandemly express mCherry and GFP, and only GFP signals are lost in acidic lysosomes subjected to mitophagy. With the ROSA26 promoter-driven rtTA, mitophagy was observed at least in heart, liver, and skeletal muscle. We investigated the relationship between mitophagy activation and pressure overload heart failure or high fat diet-induced obesity. Unexpectedly, we were unable to confirm the protective effect of mitophagy in these two pathological models. Further titration of the level of mitophagy induction is required to demonstrate the potency of the protective effects of mitophagy in disease models.

Keywords:  bioengineering; heart failure; mitophagy

DOI:  https://doi.org/10.1111/gtc.13091
Trends Endocrinol Metab. 2023 Dec 15. pii: S1043-2760(23)00243-6. [Epub ahead of print]

Mitochondrial quality control pathways sense mitochondrial protein import.

Laurie P Lee-Glover, Timothy E Shutt.

  Mitochondrial quality control (MQC) mechanisms are required to maintain a functional proteome, which enables mitochondria to perform a myriad of important cellular functions from oxidative phosphorylation to numerous other metabolic pathways. Mitochondrial protein homeostasis begins with the import of over 1000 nuclear-encoded mitochondrial proteins and the synthesis of 13 mitochondrial DNA-encoded proteins. A network of chaperones and proteases helps to fold new proteins and degrade unnecessary, damaged, or misfolded proteins, whereas more extensive damage can be removed by mitochondrial-derived vesicles (MDVs) or mitochondrial autophagy (mitophagy). Here, focusing on mechanisms in mammalian cells, we review the importance of mitochondrial protein import as a sentinel of mitochondrial function that activates multiple MQC mechanisms when impaired.

Keywords:  mitochondria; mitochondrial protein import; mitochondrial quality control; mitochondrial unfolded protein response; mitochondrial-derived vesicles; mitophagy

DOI:  https://doi.org/10.1016/j.tem.2023.11.004
J Biochem. 2023 Dec 15. pii: mvad106. [Epub ahead of print]

Mitochondrial quality control via organelle and protein degradation.

Koji Yamano, Hiroki Kinefuchi, Waka Kojima.

  Mitochondria are essential eukaryotic organelles that produce ATP as well as synthesize various macromolecules. They also participate in signaling pathways such as the innate immune response and apoptosis. These diverse functions are performed by >1000 different mitochondrial proteins. Although mitochondria are continuously exposed to potentially damaging conditions such as reactive oxygen species, proteases/peptidases localized in different mitochondrial sub-compartments, termed mitoproteases, maintain mitochondrial quality and integrity. In addition to processing incoming precursors and degrading damaged proteins, mitoproteases also regulate metabolic reactions, mitochondrial protein half-lives, and gene transcription. Impaired mitoprotease function is associated with various pathologies. In this review, we highlight recent advances in our understanding of mitochondrial quality control regulated by autophagy, ubiquitin-proteasomes, and mitoproteases.

Keywords:  autophagy; mitophagy; peptidase; protease; ubiquitin

DOI:  https://doi.org/10.1093/jb/mvad106
Trends Mol Med. 2023 Dec 19. pii: S1471-4914(23)00279-4. [Epub ahead of print]

FBXL4 mutation-caused mitochondrial DNA depletion syndrome is driven by BNIP3/BNIP3L-dependent excessive mitophagy.

Kun Gao, Xiayun Xu, Chenji Wang.

  Encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome 13 (MTDPS13) is an autosomal recessive disorder arising from biallelic F-box and leucine-rich repeat (LRR) protein 4 (FBXL4) gene mutations. Recent advances have shown that excessive BCL2 interacting protein 3 (BNIP3)/ BCL2 interacting protein 3 like (BNIP3L)-dependent mitophagy underlies the molecular pathogenesis of MTDPS13. Here, we provide an overview of these groundbreaking findings and discuss potential therapeutic strategies for this fatal disease.

Keywords:  BNIP3/BNIP3L; FBXL4; MTDPS13; mitochondria; mitophagy; ubiquitination

DOI:  https://doi.org/10.1016/j.molmed.2023.11.017
Biol Direct. 2023 Dec 20. 18(1): 86

Quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging process.

Anjila Dongol, Xi Chen, Peng Zheng, Zehra Boz Seyhan, Xu-Feng Huang.

  Senescent microglia are a distinct microglial phenotype present in aging brain that have been implicated in the progression of aging and age-related neurodegenerative diseases. However, the specific mechanisms that trigger microglial senescence are largely unknown. Quinolinic acid (QA) is a cytotoxic metabolite produced upon abnormal activation of microglia. Brain aging and age-related neurodegenerative diseases have an elevated concentration of QA. In the present study, we investigated whether QA promotes aging and aging-related phenotypes in microglia and C. elegans. Here, we demonstrate for the first time that QA, secreted by abnormal microglial stimulation, induces impaired mitophagy by inhibiting mitolysosome formation and consequently promotes the accumulation of damaged mitochondria due to reduced mitochondrial turnover in microglial cells. Defective mitophagy caused by QA drives microglial senescence and poor healthspan in C. elegans. Moreover, oxidative stress can mediate QA-induced mitophagy impairment and senescence in microglial cells. Importantly, we found that restoration of mitophagy by mitophagy inducer, urolithin A, prevents microglial senescence and improves healthspan in C. elegans by promoting mitolysosome formation and rescuing mitochondrial turnover inhibited by QA. Thus, our study indicates that mitolysosome formation impaired by QA is a significant aetiology underlying aging-associated changes. QA-induced mitophagy impairment plays a critical role in neuroinflammation and age-related diseases. Further, our study suggests that mitophagy inducers such as urolithin A may offer a promising anti-aging strategy for the prevention and treatment of neuroinflammation-associated brain aging diseases.

Keywords:  Aging; Microglia; Mitochondria; Mitolysosome; Mitophagy; Neuroinflammation; Quinolinic acid; Senescence

DOI:  https://doi.org/10.1186/s13062-023-00445-y
Cells. 2023 Dec 07. pii: 2781. [Epub ahead of print]12(24):

Disruption of Mitophagy Flux through the PARL-PINK1 Pathway by CHCHD10 Mutations or CHCHD10 Depletion.

Tian Liu, Liam Wetzel, Zexi Zhu, Pavan Kumaraguru, Viraj Gorthi, Yan Yan, Mohammed Zaheen Bukhari, Aizara Ermekbaeva, Hanna Jeon, Teresa R Kee, Jung-A Alexa Woo, David E Kang.

  Coiled-coil-helix-coiled-coil-helix domain-containing 10 (CHCHD10) is a nuclear-encoded mitochondrial protein which is primarily mutated in the spectrum of familial and sporadic amyotrophic lateral sclerosis (ALS)-frontotemporal dementia (FTD). Endogenous CHCHD10 levels decline in the brains of ALS-FTD patients, and the CHCHD10S59L mutation in Drosophila induces dominant toxicity together with PTEN-induced kinase 1 (PINK1), a protein critical for the induction of mitophagy. However, whether and how CHCHD10 variants regulate mitophagy flux in the mammalian brain is unknown. Here, we demonstrate through in vivo and in vitro models, as well as human FTD brain tissue, that ALS/FTD-linked CHCHD10 mutations (R15L and S59L) impair mitophagy flux and mitochondrial Parkin recruitment, whereas wild-type CHCHD10 (CHCHD10WT) normally enhances these measures. Specifically, we show that CHCHD10R15L and CHCHD10S59L mutations reduce PINK1 levels by increasing PARL activity, whereas CHCHD10WT produces the opposite results through its stronger interaction with PARL, suppressing its activity. Importantly, we also demonstrate that FTD brains with TAR DNA-binding protein-43 (TDP-43) pathology demonstrate disruption of the PARL-PINK1 pathway and that experimentally impairing mitophagy promotes TDP-43 aggregation. Thus, we provide herein new insights into the regulation of mitophagy and TDP-43 aggregation in the mammalian brain through the CHCHD10-PARL-PINK1 pathway.

Keywords:  CHCHD10; PARL; PINK1; TDP-43; mitophagy

DOI:  https://doi.org/10.3390/cells12242781
Neurosci Lett. 2023 Dec 13. pii: S0304-3940(23)00555-4. [Epub ahead of print]820 137596

Fingolimod exerts neuroprotection by regulating S1PR1 mediated BNIP3-PINK1-Parkin dependent mitophagy in rotenone induced mouse model of Parkinson's disease.

Shruti Rajan, Anika Sood, Rachit Jain, Pushpa Tryphena Kamatham, Dharmendra Kumar Khatri.

  The motor impairments brought on by the loss of dopaminergic neurons in the substantia nigra are the most well-known symptoms of Parkinson's disease (PD). It is believed that dopaminergic neurons are especially vulnerable to mitochondrial malfunction. For the maintenance of mitochondrial integrity, selective autophagic removal of dysfunctional mitochondria via mitophagy primarily regulated by PINK1/Parkin pathway is essential. Moreover, newer studies also implicate the role of phospholipid metabolism, such as that of Sphingosine-1-phosphate (S1P) as a contributor to PD. S1P receptors have been reported to influence mitochondrial function in neurodegenerative diseases. Fingolimod (FTY720), an S1P receptor-1 modulator has been proven effective in PD but its regulation of mitophagy in PD is still elusive. In this study, the neuroprotective effect of FTY720 by modulating mitophagy, has been explored against rotenone (ROT) induced neurotoxicity in in-vivo. The animals were randomly divided into 5 groups namely, Normal Control (NC); Disease control (DC): ROT (1.5 mg/kg); Low dose (LD): ROT + FTY720 (0.5 mg/kg); High dose (HD): ROT + FTY720 (1 mg/kg) and Vehicle control (VC): 1 % DMSO. ROT was administered through i.p. and FTY720 through p.o. for 21 days. At the end of the study, various neurobehavioral studies (rotarod test and actimeter), western blot techniques, and immunofluorescence studies were performed. FTY720 restored the neurobehavioural functions and protein expression of PINK1, Parkin and BNIP3 in ROT-induced PD mice. The results obtained in our study suggest that FTY720 has a neuroprotective effect in ROT-induced mice model of PD via PINK1-Parkin mediated mitophagy.

Keywords:  Fingolimod; Mitochondria; Mitophagy; Parkinson’s Disease; Rotenone

DOI:  https://doi.org/10.1016/j.neulet.2023.137596
Lab Invest. 2023 Dec 15. pii: S0023-6837(23)00250-7. [Epub ahead of print] 100307

The role of mitochondrial quality control in chronic obstructive pulmonary disease.

Yu-Biao Liu, Jie-Ru Hong, Nan Jiang, Ling Jin, Wen-Jing Zhong, Chen-Yu Zhang, Hui-Hui Yang, Jia-Xi Duan, Yong Zhou.

  Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity, mortality, and healthcare use worldwide with heterogeneous pathogenesis. Mitochondria, the powerhouses in cells responsible for oxidative phosphorylation and energy production, play essential roles in intracellular material metabolism, natural immunity, and cell death regulation. Therefore, it is crucial to address the urgent need for fine-tuning the regulation of mitochondrial quality to combat COPD effectively. Mitochondrial quality control (MQC) mainly refers to the selective removal of damaged or aging mitochondria and the generation of new mitochondria, which involves mitochondrial biogenesis, mitochondrial dynamics, mitophagy, etc. Mounting evidence suggests that mitochondrial dysfunction is a crucial contributor to the development and progression of COPD. This article mainly reviews the effects of MQC on COPD as well as their specific regulatory mechanisms. Finally, the therapeutic approaches of COPD via MQC are also illustrated.

Keywords:  chronic obstructive pulmonary disease; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial quality control; mitophagy

DOI:  https://doi.org/10.1016/j.labinv.2023.100307
Neural Regen Res. 2024 Aug 01. 19(8): 1828-1834

A novel mechanism of PHB2-mediated mitophagy participating in the development of Parkinson's disease.

Yongjiang Zhang, Shiyi Yin, Run Song, Xiaoyi Lai, Mengmeng Shen, Jiannan Wu, Junqiang Yan.

JOURNAL/nrgr/04.03/01300535-202408000-00037/figure1/v/2023-12-16T180322Z/r/image-tiff Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson's disease, but the regulatory mechanism remains elusive. Prohibitin-2 (PHB2) is a newly discovered autophagy receptor in the mitochondrial inner membrane, and its role in Parkinson's disease remains unclear. Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is a factor that regulates cell fate during endoplasmic reticulum stress. Parkin is regulated by PERK and is a target of the unfolded protein response. It is unclear whether PERK regulates PHB2-mediated mitophagy through Parkin. In this study, we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson's disease. We used adeno-associated virus to knockdown PHB2 expression. Our results showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson's disease. Overexpression of PHB2 inhibited these abnormalities. We also established a 1-methyl-4-phenylpyridine (MPP+)-induced SH-SY5Y cell model of Parkinson's disease. We found that overexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3, and promoted mitophagy. In addition, MPP+ regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK. These findings suggest that PHB2 participates in the development of Parkinson's disease by interacting with endoplasmic reticulum stress and Parkin.

DOI: https://doi.org/10.4103/1673-5374.389356