bims-tofagi 2024-10-20 papers

on Mitophagy

Issue of 2024–10–20
eight papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea

Mitophagy as a guardian against cellular aging.
Autophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates.
Enhancing CNS mitophagy: drug development and disease-relevant models.
Deficiency of parkin causes neurodegeneration and accumulation of pathological α-synuclein in monkey models.
Autophagy, aging, and age-related neurodegeneration.
RABIF promotes hepatocellular carcinoma progression through regulation of mitophagy and glycolysis.
Outer mitochondrial membrane E3 Ub ligase MARCH5 controls de novo peroxisome biogenesis.
Regulation of the NLRP3 inflammasome by autophagy and mitophagy.

Autophagy. 2024 Oct 14. 1-3

Mitophagy as a guardian against cellular aging.

Tetsushi Kataura, Niall Wilson, Gailing Ma, Viktor I Korolchuk.

  Mitophagy, the selective autophagic clearance of damaged mitochondria, is considered vital for maintaining mitochondrial quality and cellular homeostasis; however, its molecular mechanisms, particularly under basal conditions, and its role in cellular physiology remain poorly characterized. We recently demonstrated that basal mitophagy is a key feature of primary human cells and is downregulated by immortalization, suggesting its dependence on the primary cell state. Mechanistically, we demonstrated that the PINK1-PRKN-SQSTM1 pathway regulates basal mitophagy, with SQSTM1 sensing superoxide-enriched mitochondria through its redox-sensitive cysteine residues, which mediate SQSTM1 oligomerization and mitophagy activation. We developed STOCK1N-57534, a small molecule that targets and promotes this SQSTM1 activation mechanism. Treatment with STOCK1N-57534 reactivates mitophagy downregulated in senescent and naturally aged donor-derived primary cells, improving cellular senescence(-like) phenotypes. Our findings highlight that basal mitophagy is protective against cellular senescence and aging, positioning its pharmacological reactivation as a promising anti-aging strategy.Abbreviation: IR: ionizing radiation; ROS: reactive oxygen species; SARs: selective autophagy receptors.

Keywords:  Aging; SQSTM1/p62; autophagy; mitochondria; mitophagy; senescence

DOI:  https://doi.org/10.1080/15548627.2024.2414461
EMBO J. 2024 Oct 17.

Autophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates.

Zi Yang, Saori R Yoshii, Yuji Sakai, Jing Zhang, Haruka Chino, Roland L Knorr, Noboru Mizushima.

  During PINK1- and Parkin-mediated mitophagy, autophagy adaptors are recruited to damaged mitochondria to promote their selective degradation. Autophagy adaptors such as optineurin (OPTN) and NDP52 facilitate mitophagy by recruiting the autophagy-initiation machinery, and assisting engulfment of damaged mitochondria through binding to ubiquitinated mitochondrial proteins and autophagosomal ATG8 family proteins. Here, we demonstrate that OPTN and NDP52 form sheet-like phase-separated condensates with liquid-like properties on the surface of ubiquitinated mitochondria. The dynamic and liquid-like nature of OPTN condensates is important for mitophagy activity, because reducing the fluidity of OPTN-ubiquitin condensates suppresses the recruitment of ATG9 vesicles and impairs mitophagy. Based on these results, we propose a dynamic liquid-like, rather than a stoichiometric, model of autophagy adaptors to explain the interactions between autophagic membranes (i.e., ATG9 vesicles and isolation membranes) and mitochondrial membranes during Parkin-mediated mitophagy. This model underscores the importance of liquid-liquid phase separation in facilitating membrane-membrane contacts, likely through the generation of capillary forces.

Keywords:  Autophagy; Liquid–Liquid Phase Separation; Mitophagy; Optineurin; Wetting

DOI:  https://doi.org/10.1038/s44318-024-00272-5
Trends Pharmacol Sci. 2024 Oct 16. pii: S0165-6147(24)00187-1. [Epub ahead of print]

Enhancing CNS mitophagy: drug development and disease-relevant models.

Krishayant S Dhar, Brendan Townsend, Andrew P Montgomery, Jonathan J Danon, Julia K Pagan, Michael Kassiou.

  Mitophagy, the selective degradation of mitochondria, is impaired in many neurodegenerative diseases (NDs), resulting in an accumulation of dysfunctional mitochondria and neuronal damage. Although enhancing mitophagy shows promise as a therapeutic strategy, the clinical significance of mitophagy activators remains uncertain due to limited understanding and poor representation of mitophagy in the central nervous system (CNS). This review explores recent insights into which mitophagy pathways to target and the extent of modulation necessary to be therapeutic towards NDs. We also highlight the complexities of mitophagy in the CNS, highlighting the need for disease-relevant models. Last, we outline crucial aspects of in vitro models to consider during drug discovery, aiming to bridge the gap between preclinical research and clinical applications in treating NDs through mitophagy modulation.

Keywords:  central nervous system; clinical relevance; disease models; drug development; mitochondrial dysfunction; mitophagy; neurodegenerative diseases

DOI:  https://doi.org/10.1016/j.tips.2024.09.002
J Clin Invest. 2024 Oct 15. pii: e179633. [Epub ahead of print]134(20):

Deficiency of parkin causes neurodegeneration and accumulation of pathological α-synuclein in monkey models.

Rui Han, Qi Wang, Xin Xiong, Xiusheng Chen, Zhuchi Tu, Bang Li, Fei Zhang, Chunyu Chen, Mingtian Pan, Ting Xu, Laiqiang Chen, Zhifu Wang, Yanting Liu, Dajian He, Xiangyu Guo, Feng He, Peng Wu, Peng Yin, Yunbo Liu, Xiaoxin Yan, Shihua Li, Xiao-Jiang Li, Weili Yang.

  Parkinson's disease (PD) is characterized by age-dependent neurodegeneration and the accumulation of toxic phosphorylated α-synuclein (pS129-α-syn). The mechanisms underlying these crucial pathological changes remain unclear. Mutations in parkin RBR E3 ubiquitin protein ligase (PARK2), the gene encoding parkin that is phosphorylated by PTEN-induced putative kinase 1 (PINK1) to participate in mitophagy, cause early onset PD. However, current parkin-KO mouse and pig models do not exhibit neurodegeneration. In the current study, we utilized CRISPR/Cas9 technology to establish parkin-deficient monkey models at different ages. We found that parkin deficiency leads to substantia nigra neurodegeneration in adult monkey brains and that parkin phosphorylation decreases with aging, primarily due to increased insolubility of parkin. Phosphorylated parkin is important for neuroprotection and the reduction of pS129-α-syn. Consistently, overexpression of WT parkin, but not a mutant form that cannot be phosphorylated by PINK1, reduced the accumulation of pS129-α-syn. These findings identify parkin phosphorylation as a key factor in PD pathogenesis and suggest it as a promising target for therapeutic interventions.

Keywords:  Aging; Neuroscience; Parkinson disease

DOI:  https://doi.org/10.1172/JCI179633
Neuron. 2024 Oct 08. pii: S0896-6273(24)00663-9. [Epub ahead of print]

Autophagy, aging, and age-related neurodegeneration.

Jennifer E Palmer, Niall Wilson, Sung Min Son, Pawel Obrocki, Lidia Wrobel, Matea Rob, Michael Takla, Viktor I Korolchuk, David C Rubinsztein.

  Autophagy is a conserved mechanism that degrades damaged or superfluous cellular contents and enables nutrient recycling under starvation conditions. Many neurodegeneration-associated proteins are autophagy substrates, and autophagy upregulation ameliorates disease in many animal models of neurodegeneration by enhancing the clearance of toxic proteins, proinflammatory molecules, and dysfunctional organelles. Autophagy inhibition also induces neuronal and glial senescence, a phenomenon that occurs with increasing age in non-diseased brains as well as in response to neurodegeneration-associated stresses. However, aging and many neurodegeneration-associated proteins and mutations impair autophagy. This creates a potentially detrimental feedback loop whereby the accumulation of these disease-associated proteins impairs their autophagic clearance, facilitating their further accumulation and aggregation. Thus, understanding how autophagy interacts with aging, senescence, and neurodegenerative diseases in a temporal, cellular, and genetic context is important for the future clinical application of autophagy-modulating therapies in aging and neurodegeneration.

Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; aging; autophagy; frontotemporal dementia; motor neuron disease; neurodegeneration; senescence

DOI:  https://doi.org/10.1016/j.neuron.2024.09.015
Commun Biol. 2024 Oct 16. 7(1): 1333

RABIF promotes hepatocellular carcinoma progression through regulation of mitophagy and glycolysis.

Ning Feng, Rui Zhang, Xin Wen, Wei Wang, Nie Zhang, Junnian Zheng, Longzhen Zhang, Nianli Liu.

The RAB interacting factor (RABIF) is a putative guanine nucleotide exchange factor that also functions as a RAB-stabilizing holdase chaperone. It has been implicated in pathogenesis of several cancers. However, the functional role and molecular mechanism of RABIF in hepatocellular carcinoma (HCC) are not entirely known. Here, we demonstrate an upregulation of RABIF in patients with HCC, correlating with a poor prognosis. RABIF inhibition results in decreased HCC cell growth both in vitro and in vivo. Our study reveals that depleting RABIF attenuates the STOML2-PARL-PGAM5 axis-mediated mitophagy. Consequently, this reduction in mitophagy results in diminished mitochondrial reactive oxygen species (mitoROS) production, thereby alleviating the HIF1α-mediated downregulation of glycolytic genes HK1, HKDC1, and LDHB. Additionally, we illustrate that RABIF regulates glucose uptake by controlling RAB10 expression. Importantly, the knockout of RABIF or blockade of mitophagy sensitizes HCC cells to sorafenib. This study uncovers a previously unrecognized role of RABIF crucial for HCC growth and identifies it as a potential therapeutic target.

DOI: https://doi.org/10.1038/s42003-024-07028-1
Dev Cell. 2024 Oct 15. pii: S1534-5807(24)00538-0. [Epub ahead of print]

Outer mitochondrial membrane E3 Ub ligase MARCH5 controls de novo peroxisome biogenesis.

Nicolas Verhoeven, Yumiko Oshima, Etienne Cartier, Claudia Christiane Bippes, Albert Neutzner, Liron Boyman, Mariusz Karbowski.

  We report that the outer mitochondrial membrane (OMM)-associated E3 Ub ligase MARCH5 is vital for generating mitochondria-derived pre-peroxisomes. In human immortalized cells, MARCH5 knockout leads to the accumulation of immature peroxisomes, reduced fatty-acid-induced peroxisomal biogenesis, and abnormal peroxisome biogenesis in MARCH5/Pex14 and MARCH5/Pex3 dko cells. Upon fatty-acid-induced peroxisomal biogenesis, MARCH5 redistributes to peroxisomes, and ubiquitination activity-deficient mutants of MARCH5 accumulate on peroxisomes containing high levels of the OMM protein Tom20 (mitochondria-derived pre-peroxisomes). Similarly, depletion of peroxisome biogenesis factor Pex14 leads to the accumulation of MARCH5- and Tom20-positive pre-peroxisomes, whereas no peroxisomes are detected in MARCH5/Pex14 dko cells. Inconsistent with MARCH5 merely acting as a quality factor, mitochondrial decline is not evident in tested models. Furthermore, reduced expression of peroxisomal proteins is detected in MARCH5-/- cells, whereas some of these proteins are stabilized in peroxisome biogenesis deficiency models lacking MARCH5 expression. Thus, MARCH5 is central for mitochondria-dependent peroxisome biogenesis.

Keywords:  MARCH5; Pex14; Pex3; Ub E3 ligase; biogenesis; metabolic adaptation; mitochondria; mitochondria-derived pre-peroxisomes; peroxisomes

DOI:  https://doi.org/10.1016/j.devcel.2024.09.010
Immunol Rev. 2024 Oct 17.

Regulation of the NLRP3 inflammasome by autophagy and mitophagy.

Suman Gupta, Suzanne L Cassel, Fayyaz S Sutterwala, Jargalsaikhan Dagvadorj.

  The NLRP3 inflammasome is a multiprotein complex that upon activation by the innate immune system drives a broad inflammatory response. The primary initial mediators of this response are pro-IL-1β and pro-IL-18, both of which are in an inactive form. Formation and activation of the NLRP3 inflammasome activates caspase-1, which cleaves pro-IL-1β and pro-IL-18 and triggers the formation of gasdermin D pores. Gasdermin D pores allow for the secretion of active IL-1β and IL-18 initiating the organism-wide inflammatory response. The NLRP3 inflammasome response can be beneficial to the host; however, if the NLRP3 inflammasome is inappropriately activated it can lead to significant pathology. While the primary components of the NLRP3 inflammasome are known, the precise details of assembly and activation are less well defined and conflicting. Here, we discuss several of the proposed pathways of activation of the NLRP3 inflammasome. We examine the role of subcellular localization and the reciprocal regulation of the NLRP3 inflammasome by autophagy. We focus on the roles of mitochondria and mitophagy in activating and regulating the NLRP3 inflammasome. Finally, we detail the impact of pathologic NLRP3 responses in the development and manifestations of pulmonary disease.

Keywords:  NLRP3; caspase‐1; inflammasome; lung injury; mitochondria

DOI:  https://doi.org/10.1111/imr.13410