bims-tofagi 2024-04-07 papers

on Mitophagy

Issue of 2024–04–07
six papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea

PINK1 deficiency alters muscle stem cell fate decision and muscle regenerative capacity.
Cytosolic retention of HtrA2 during mitochondrial protein import stress triggers the DELE1-HRI pathway.
Identification and structural characterization of small molecule inhibitors of PINK1.
Mitophagy and spermatogenesis: Role and mechanisms.
Chronic replication stress invokes mitochondria dysfunction via impaired parkin activity.
USP26 promotes colorectal cancer tumorigenesis by restraining PRKN-mediated mitophagy.

Stem Cell Reports. 2024 Mar 26. pii: S2213-6711(24)00079-1. [Epub ahead of print]

PINK1 deficiency alters muscle stem cell fate decision and muscle regenerative capacity.

George Cairns, Madhavee Thumiah-Mootoo, Mah Rukh Abbasi, Melissa Gourlay, Jeremy Racine, Nikita Larionov, Alexandre Prola, Mireille Khacho, Yan Burelle.

  Maintenance of mitochondrial function plays a crucial role in the regulation of muscle stem cell (MuSC), but the underlying mechanisms remain ill defined. In this study, we monitored mitophagy in MuSCS under various myogenic states and examined the role of PINK1 in maintaining regenerative capacity. Results indicate that quiescent MuSCs actively express mitophagy genes and exhibit a measurable mitophagy flux and prominent mitochondrial localization to autophagolysosomes, which become rapidly decreased during activation. Genetic disruption of Pink1 in mice reduces PARKIN recruitment to mitochondria and mitophagy in quiescent MuSCs, which is accompanied by premature activation/commitment at the expense of self-renewal and progressive loss of muscle regeneration, but unhindered proliferation and differentiation capacity. Results also show that impaired fate decisions in PINK1-deficient MuSCs can be restored by scavenging excess mitochondrial ROS. These data shed light on the regulation of mitophagy in MuSCs and position PINK1 as an important regulator of their mitochondrial properties and fate decisions.

Keywords:  fate decision; mitochondria; mitochondrial quality control; mitophagy; muscle regeneration; muscle stem cells

DOI:  https://doi.org/10.1016/j.stemcr.2024.03.004
Commun Biol. 2024 Mar 30. 7(1): 391

Cytosolic retention of HtrA2 during mitochondrial protein import stress triggers the DELE1-HRI pathway.

Paul Y Bi, Samuel A Killackey, Linus Schweizer, Damien Arnoult, Dana J Philpott, Stephen E Girardin.

Mitochondrial stress inducers such as carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and oligomycin trigger the DELE1-HRI branch of the integrated stress response (ISR) pathway. Previous studies performed using epitope-tagged DELE1 showed that these stresses induced the cleavage of DELE1 to DELE1-S, which stimulates HRI. Here, we report that mitochondrial protein import stress (MPIS) is an overarching stress that triggers the DELE1-HRI pathway, and that endogenous DELE1 could be cleaved into two forms, DELE1-S and DELE1-VS, the latter accumulating only upon non-depolarizing MPIS. Surprisingly, while the mitochondrial protease OMA1 was crucial for DELE1 cleavage in HeLa cells, it was dispensable in HEK293T cells, suggesting that multiple proteases may be involved in DELE1 cleavage. In support, we identified a role for the mitochondrial protease, HtrA2, in mediating DELE1 cleavage into DELE1-VS, and showed that a Parkinson's disease (PD)-associated HtrA2 mutant displayed reduced DELE1 processing ability, suggesting a novel mechanism linking PD pathogenesis to mitochondrial stress. Our data further suggest that DELE1 is likely cleaved into DELE1-S in the cytosol, while the DELE1-VS form might be generated during halted translocation into mitochondria. Together, this study identifies MPIS as the overarching stress detected by DELE1 and identifies a novel role for HtrA2 in DELE1 processing.

DOI: https://doi.org/10.1038/s42003-024-06107-7
Sci Rep. 2024 04 02. 14(1): 7739

Identification and structural characterization of small molecule inhibitors of PINK1.

Shafqat Rasool, Tara Shomali, Luc Truong, Nathalie Croteau, Simon Veyron, Bernardo A Bustillos, Wolfdieter Springer, Fabienne C Fiesel, Jean-François Trempe.

  Mutations in PINK1 and Parkin cause early-onset Parkinson's Disease (PD). PINK1 is a kinase which functions as a mitochondrial damage sensor and initiates mitochondrial quality control by accumulating on the damaged organelle. There, it phosphorylates ubiquitin, which in turn recruits and activates Parkin, an E3 ubiquitin ligase. Ubiquitylation of mitochondrial proteins leads to the autophagic degradation of the damaged organelle. Pharmacological modulation of PINK1 constitutes an appealing avenue to study its physiological function and develop therapeutics. In this study, we used a thermal shift assay with insect PINK1 to identify small molecules that inhibit ATP hydrolysis and ubiquitin phosphorylation. PRT062607, an SYK inhibitor, is the most potent inhibitor in our screen and inhibits both insect and human PINK1, with an IC50 in the 0.5-3 µM range in HeLa cells and dopaminergic neurons. The crystal structures of insect PINK1 bound to PRT062607 or CYC116 reveal how the compounds interact with the ATP-binding pocket. PRT062607 notably engages with the catalytic aspartate and causes a destabilization of insert-2 at the autophosphorylation dimer interface. While PRT062607 is not selective for PINK1, it provides a scaffold for the development of more selective and potent inhibitors of PINK1 that could be used as chemical probes.

Keywords:  Inhibitor; Kinase; Mitochondria; PTEN‐induced kinase 1 (PINK1); Parkinson disease; Ubiquitin

DOI:  https://doi.org/10.1038/s41598-024-58285-3
Biochem Biophys Rep. 2024 Jul;38 101698

Mitophagy and spermatogenesis: Role and mechanisms.

Damilare Emmanuel Rotimi, Matthew Iyobhebhe, Elizabeth Temidayo Oluwayemi, Ikponmwosa Owen Evbuomwan, Rotdelmwa Maimako Asaleye, Oluwafemi Adeleke Ojo, Oluyomi Stephen Adeyemi.

  The mitophagy process, a type of macroautophagy, is the targeted removal of mitochondria. It is a type of autophagy exclusive to mitochondria, as the process removes defective mitochondria one by one. Mitophagy serves as an additional level of quality control by using autophagy to remove superfluous mitochondria or mitochondria that are irreparably damaged. During spermatogenesis, mitophagy can influence cell homeostasis and participates in a variety of membrane trafficking activities. Crucially, it has been demonstrated that defective mitophagy can impede spermatogenesis. Despite an increasing amount of evidence suggesting that mitophagy and mitochondrial dynamics preserve the fundamental level of cellular homeostasis, little is known about their role in developmentally controlled metabolic transitions and differentiation. It has been observed that male infertility is a result of mitophagy's impact on sperm motility. Furthermore, certain proteins related to autophagy have been shown to be present in mammalian spermatozoa. The mitochondria are the only organelle in sperm that can produce reactive oxygen species and finally provide energy for sperm movement. Furthermore, studies have shown that inhibited autophagy-infected spermatozoa had reduced motility and increased amounts of phosphorylated PINK1, TOM20, caspase 3/7, and AMPK. Therefore, in terms of reproductive physiology, mitophagy is the removal of mitochondria derived from sperm and the following preservation of mitochondria that are exclusively maternal.

Keywords:  Autophagy; Male infertility; Reproductive health; Spermatogenesis

DOI:  https://doi.org/10.1016/j.bbrep.2024.101698
Sci Rep. 2024 Apr 03. 14(1): 7877

Chronic replication stress invokes mitochondria dysfunction via impaired parkin activity.

Tsuyoshi Kawabata, Reiko Sekiya, Shinji Goto, Tao-Sheng Li.

Replication stress is a major contributor to tumorigenesis because it provides a source of chromosomal rearrangements via recombination events. PARK2, which encodes parkin, a regulator of mitochondrial homeostasis, is located on one of the common fragile sites that are prone to rearrangement by replication stress, indicating that replication stress may potentially impact mitochondrial homeostasis. Here, we show that chronic low-dose replication stress causes a fixed reduction in parkin expression, which is associated with mitochondrial dysfunction, indicated by an increase in mtROS. Consistent with the major role of parkin in mitophagy, reduction in parkin protein expression was associated with a slight decrease in mitophagy and changes in mitochondrial morphology. In contrast, cells expressing ectopic PARK2 gene does not show mtROS increases and changes in mitochondrial morphology even after exposure to chronic replication stress, suggesting that intrinsic fragility at PARK2 loci associated with parkin reduction is responsible for mitochondrial dysfunction caused by chronic replication stress. As endogenous replication stress and mitochondrial dysfunction are both involved in multiple pathophysiology, our data support the therapeutic development of recovery of parkin expression in human healthcare.

DOI: https://doi.org/10.1038/s41598-024-58656-w
Oncogene. 2024 Apr 02.

USP26 promotes colorectal cancer tumorigenesis by restraining PRKN-mediated mitophagy.

Qi Wu, Zhihong Wang, Siqi Chen, Xiaowei She, Shengyu Zhu, Pengcheng Li, Lang Liu, Chongchong Zhao, Kangdi Li, Anyi Liu, Changsheng Huang, Yaqi Chen, Fuqing Hu, Guihua Wang, Junbo Hu.

Deubiquitinating enzymes (DUBs) are promising targets for cancer therapy because of their pivotal roles in various physiological and pathological processes. Among these, ubiquitin-specific peptidase 26 (USP26) is a protease with crucial regulatory functions. Our study sheds light on the upregulation of USP26 in colorectal cancer (CRC), in which its increased expression correlates with an unfavorable prognosis. Herein, we evidenced the role of USP26 in promoting CRC tumorigenesis in a parkin RBR E3 ubiquitin-protein ligase (PRKN) protein-dependent manner. Our investigation revealed that USP26 directly interacted with PRKN protein, facilitating its deubiquitination, and subsequently reducing its activity. Additionally, we identified the K129 site on PRKN as a specific target for USP26-mediated deubiquitination. Our research highlights that a K-to-R mutation at the site on PRKN diminishes its potential for activation and ability to mediate mitophagy. In summary, our findings underscore the significance of USP26-mediated deubiquitination in restraining the activation of the PRKN-mediated mitophagy pathway, ultimately driving CRC tumorigenesis. This study not only elucidated the multifaceted role of USP26 in CRC but also introduced a promising avenue for therapeutic exploration through the development of small molecule inhibitors targeting USP26. This strategy holds promise as a novel therapeutic approach for CRC.

DOI: https://doi.org/10.1038/s41388-024-03009-0