bims-tofagi 2024-02-04 papers

on Mitophagy

Issue of 2024‒02‒04
seven papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea

Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging.
Comparative analysis of primate and pig cells reveals primate-specific PINK1 expression and phosphorylation.
PINK1 knockout rats show premotor cognitive deficits measured through a complex maze.
Mitophagy in plants: Emerging regulators of mitochondrial targeting for selective autophagy.
Deregulated mitochondrial quality control, the heel of Achilles in elucidating the role of autophagy in SARM1-mediated axon degeneration.
Regulation of ULK1 by WTAP/IGF2BP3 axis enhances mitophagy and progression in epithelial ovarian cancer.
The clarithromycin-binding proteins NIPSNAP1 and 2 regulate cytokine production through mitochondrial quality control.

Nat Commun. 2024 Jan 27. 15(1): 830

Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging.

Juan Ignacio Jiménez-Loygorri, Beatriz Villarejo-Zori, Álvaro Viedma-Poyatos, Juan Zapata-Muñoz, Rocío Benítez-Fernández, María Dolores Frutos-Lisón, Francisco A Tomás-Barberán, Juan Carlos Espín, Estela Area-Gómez, Aurora Gomez-Duran, Patricia Boya.

Macroautophagy decreases with age, and this change is considered a hallmark of the aging process. It remains unknown whether mitophagy, the essential selective autophagic degradation of mitochondria, also decreases with age. In our analysis of mitophagy in multiple organs in the mito-QC reporter mouse, mitophagy is either increased or unchanged in old versus young mice. Transcriptomic analysis shows marked upregulation of the type I interferon response in the retina of old mice, which correlates with increased levels of cytosolic mtDNA and activation of the cGAS/STING pathway. Crucially, these same alterations are replicated in primary human fibroblasts from elderly donors. In old mice, pharmacological induction of mitophagy with urolithin A attenuates cGAS/STING activation and ameliorates deterioration of neurological function. These findings point to mitophagy induction as a strategy to decrease age-associated inflammation and increase healthspan.

DOI: https://doi.org/10.1038/s41467-024-45044-1
Zool Res. 2024 Mar 18. pii: 2095-8137(2024)02-0242-11. [Epub ahead of print]45(2): 242-252

Comparative analysis of primate and pig cells reveals primate-specific PINK1 expression and phosphorylation.

Xiu-Sheng Chen, Rui Han, Yan-Ting Liu, Wei Huang, Qi Wang, Xin Xiong, Ying Zhang, Jian-Guo Zhao, Shi-Hua Li, Xiao-Jiang Li, Wei-Li Yang.

  PTEN-induced putative kinase 1 (PINK1), a mitochondrial kinase that phosphorylates Parkin and other proteins, plays a crucial role in mitophagy and protection against neurodegeneration. Mutations in PINK1 and Parkin can lead to loss of function and early onset Parkinson's disease. However, there is a lack of strong in vivo evidence in rodent models to support the theory that loss of PINK1 affects mitophagy and induces neurodegeneration. Additionally, PINK1 knockout pigs ( Sus scrofa) do not appear to exhibit neurodegeneration. In our recent work involving non-human primates, we found that PINK1 is selectively expressed in primate brains, while absent in rodent brains. To extend this to other species, we used multiple antibodies to examine the expression of PINK1 in pig tissues. In contrast to tissues from cynomolgus monkeys ( Macaca fascicularis), our data did not convincingly demonstrate detectable PINK1 expression in pig tissues. Knockdown of PINK1 in cultured pig cells did not result in altered Parkin and BAD phosphorylation, as observed in cultured monkey cells. A comparison of monkey and pig striatum revealed more PINK1-phosphorylated substrates in the monkey brain. Consistently, PINK1 knockout in pigs did not lead to obvious changes in the phosphorylation of Parkin and BAD. These findings provide new evidence that PINK1 expression is specific to primates, underscoring the importance of non-human primates in investigating PINK1 function and pathology related to PINK1 deficiency.

Keywords:  Mitochondria; Non-human primates; PINK1; Parkin; Phosphorylation; Pigs

DOI:  https://doi.org/10.24272/j.issn.2095-8137.2023.241
bioRxiv. 2024 Jan 19. pii: 2024.01.18.576285. [Epub ahead of print]

PINK1 knockout rats show premotor cognitive deficits measured through a complex maze.

Isabel Soto, Vicki A Nejtek, David P Siderovski, Michael F Salvatore.

Cognitive decline in Parkinson's disease (PD) emerges up to 10 years before clinical recognition. Neurobiological mechanisms underlying premotor cognitive impairment in PD can potentially be examined in the PINK1 -/- rat, which exhibits a protracted motor onset. To enhance translation to human PD cognitive assessments, we tested a modified multiple T-maze, which measures cognitive flexibility similarly to the Trail-Making Test in humans. Like human PD outcomes, PINK1 -/- rats made more errors and took longer to complete the maze than wild types. Thus, we have identified a potential tool for assessing cross-species translation of cognitive functioning in an established PD animal model.

DOI: https://doi.org/10.1101/2024.01.18.576285
J Microsc. 2024 Jan 31.

Mitophagy in plants: Emerging regulators of mitochondrial targeting for selective autophagy.

Patrick J Duckney, Pengwei Wang, Patrick J Hussey.

  The degradation and turnover of mitochondria is fundamental to Eukaryotes and is a key homeostatic mechanism for maintaining functional mitochondrial populations. Autophagy is an important pathway by which mitochondria are degraded, involving their sequestration into membrane-bound autophagosomes and targeting to lytic endosomal compartments (the lysosome in animals, the vacuole in plants and yeast). Selective targeting of mitochondria for autophagy, also known as mitophagy, distinguishes mitochondria from other cell components for degradation and is necessary for the regulation of mitochondria-specific cell processes. In mammals and yeast, mitophagy has been well characterised and is regulated by numerous pathways with diverse and important functions in the regulation of cell homeostasis, metabolism and responses to specific stresses. In contrast, we are only just beginning to understand the importance and functions of mitophagy in plants, chiefly as the proteins that target mitochondria for autophagy in plants are only recently emerging. Here, we discuss the current progress of our understanding of mitophagy in plants, the importance of mitophagy for plant life and the regulatory autophagy proteins involved in mitochondrial degradation. In particular, we will discuss the recent emergence of mitophagy receptor proteins that selectively target mitochondria for autophagy, and discuss the missing links in our knowledge of mitophagy-regulatory proteins in plants compared to animals and yeast.

Keywords:  Arabidopsis; TRB1; TraB; autophagy; contact site; homeostasis; mitochondria; mitophagy; plant; stress

DOI:  https://doi.org/10.1111/jmi.13267
J Neurosci Res. 2024 Jan;102(1): e25292

Deregulated mitochondrial quality control, the heel of Achilles in elucidating the role of autophagy in SARM1-mediated axon degeneration.

Shuai Wang, Yifan Zhang, Mingxue Song, Xiulan Zhao, Fuyong Song.

  Autophagic dysfunction in neurodegenerative diseases is being extensively studied, yet the exact mechanism of macroautophagy/autophagy in axon degeneration is still elusive. A recent study by Kim et al. links autophagic stress to the sterile α and toll/interleukin 1 receptor motif containing protein 1 (SARM1)-dependent core axonal degeneration program, providing a new insight into the role of autophagy in axon degeneration. In the classical Wallerian axon degeneration model of axotomy, disruption of axonal transport destroys the coordinated activity of pro-survival and pro-degenerative factors in the axoplasm and activates the NADase activity of SARM1, thus triggering the axonal self-destruction program. However, the mechanism for SARM1 activation in the chronic neurodegenerative disorders is more complex. Mitochondrial defects and oxidative stress contribute to the activation of SARM1, while mitophagy can inhibit mitochondrial dysfunction and promote the clearance of SARM1 on mitochondria, thus protecting against neuronal degeneration. Therefore, in-depth elucidation of the underlying mechanisms of mitophagy during axonal degeneration can help develop promising strategies for the prevention and treatment of various neurodegenerative disorders.

Keywords:  SARM1; autophagy; axon degeneration; mitochondrial dysfunction; mitophagy

DOI:  https://doi.org/10.1002/jnr.25292
Cell Death Dis. 2024 Jan 29. 15(1): 97

Regulation of ULK1 by WTAP/IGF2BP3 axis enhances mitophagy and progression in epithelial ovarian cancer.

Jiao Wang, Fei Zheng, Dandan Wang, Qing Yang.

There is a pressing need for innovative therapeutic strategies for patients with epithelial ovarian cancer (EOC). Previous studies have shown that UNC-51-like kinase 1 (ULK1), a serine/threonine kinase, is crucial in regulating cellular autophagy and mitophagy across various tumor types. However, the clinical implications, biological functions, and potential mechanisms of ULK1 in EOC remain poorly understood. This study demonstrates that ULK1 expression is upregulated in EOC tissue samples and EOC cell lines, with increased ULK1 expression correlating with poor prognosis. Functionally, overexpressed ULK1 enhances the proliferation and migration abilities of EOC cells both in vitro and in vivo. Mechanistically, ULK1 was identified as an m6A target of WTAP. WTAP-mediated m6A modification of ULK1 enhanced its mRNA stability in an IGF2BP3-dependent manner, leading to elevated ULK1 expression and enhanced mitophagy in EOC. In summary, our research reveals that the WTAP/IGF2BP3-ULK1 axis significantly influences protective mitophagy in EOC, contributing to its progression. Therefore, the regulatory mechanisms and biological function of ULK1 identify it as a potential molecular target for therapeutic intervention in EOC.

DOI: https://doi.org/10.1038/s41419-024-06477-0
Sci Rep. 2024 01 29. 14(1): 2354

The clarithromycin-binding proteins NIPSNAP1 and 2 regulate cytokine production through mitochondrial quality control.

Soh Yamamoto, Noriko Ogasawara, Yukari Mitsuhashi, Kenichi Takano, Shin-Ichi Yokota.

The mechanism underlying the anti-inflammatory effect of macrolide antibiotics, such as clarithromycin (CAM), remains to be clarified. The CAM-binding proteins 4-nitrophenylphosphatase domain and non-neuronal synaptosomal associated protein 25 (SNAP25)-like protein homolog (NIPSNAP) 1 and 2 are involved in the immune response and mitochondrial homeostasis. However, the axis between CAM-NIPSNAP-mitochondria and Toll-like receptor (TLR) and their molecular mechanisms remain unknown. In this study, we sought to elucidate the relationship between mitochondrial homeostasis mediated by NIPSNAP1 and 2 and the immunomodulatory effect of CAM. NIPSNAP1 or 2 knockdown (KD) by RNA interference impaired TLR4-mediated interleukin-8 (IL-8) production. Similar impairment was observed upon treatment with mitochondrial function inhibitors. However, IL-8 secretion was not impaired in NIPSNAP1 and 2 individual knockout (KO) and double KO (DKO) cells. Moreover, the oxygen consumption rate (OCR) in mitochondria measured using a flex analyzer was significantly reduced in NIPSNAP1 or 2 KD cells, but not in DKO cells. CAM also dose-dependently reduced the OCR. These results indicate that CAM suppresses the IL-8 production via the mitochondrial quality control regulated by temporary functional inhibition of NIPSNAP1 and 2. Our findings provide new insight into the mechanisms underlying cytokine production, including the TLR-mitochondria axis, and the immunomodulatory effects of macrolides.

DOI: https://doi.org/10.1038/s41598-024-52582-7