bims-tofagi 2024-03-24 papers

on Mitophagy

Issue of 2024‒03‒24
seven papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea

Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons.
The SCF-FBW7β E3 ligase mediates ubiquitination and degradation of the serine/threonine protein kinase PINK1.
Integrating the response to stressed mitochondria.
AMPK and insulin control the switch between mitochondrial hitchhiking of Pink1 mRNA and mitophagy in neurons.
miR-218-5p and doxorubicin combination enhances anticancer activity in breast cancer cells through Parkin-dependent mitophagy inhibition.
Neuro-modulatory impact of felodipine against experimentally-induced Parkinson's disease: Possible contribution of PINK1-Parkin mitophagy pathway.
Interplay of mitochondria associated membrane proteins and autophagy: Implications in neurodegeneration.

Nat Metab. 2024 Mar 19.

Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons.

J Tabitha Hees, Simone Wanderoy, Jana Lindner, Marlena Helms, Hariharan Murali Mahadevan, Angelika B Harbauer.

Mitochondrial quality control failure is frequently observed in neurodegenerative diseases. The detection of damaged mitochondria by stabilization of PTEN-induced kinase 1 (PINK1) requires transport of Pink1 messenger RNA (mRNA) by tethering it to the mitochondrial surface. Here, we report that inhibition of AMP-activated protein kinase (AMPK) by activation of the insulin signalling cascade prevents Pink1 mRNA binding to mitochondria. Mechanistically, AMPK phosphorylates the RNA anchor complex subunit SYNJ2BP within its PDZ domain, a phosphorylation site that is necessary for its interaction with the RNA-binding protein SYNJ2. Notably, loss of mitochondrial Pink1 mRNA association upon insulin addition is required for PINK1 protein activation and its function as a ubiquitin kinase in the mitophagy pathway, thus placing PINK1 function under metabolic control. Induction of insulin resistance in vitro by the key genetic Alzheimer risk factor apolipoprotein E4 retains Pink1 mRNA at the mitochondria and prevents proper PINK1 activity, especially in neurites. Our results thus identify a metabolic switch controlling Pink1 mRNA localization and PINK1 activity via insulin and AMPK signalling in neurons and propose a mechanistic connection between insulin resistance and mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s42255-024-01007-w
J Biol Chem. 2024 Mar 18. pii: S0021-9258(24)01693-4. [Epub ahead of print] 107198

The SCF-FBW7β E3 ligase mediates ubiquitination and degradation of the serine/threonine protein kinase PINK1.

Seo Jeong Jeon, Kwang Chul Chung.

  Understanding the mechanisms that govern the stability of functionally crucial proteins is essential for various cellular processes, development, and overall cell viability. Disturbances in protein homeostasis are linked to the pathogenesis of neurodegenerative diseases (NDDs). PINK1, a protein kinase, plays a significant role in mitochondrial quality control and cellular stress response, and its mutated forms lead to early-onset Parkinson's disease (PD). Despite its importance, the specific mechanisms regulating PINK1 protein stability have remained unclear. This study reveals a cytoplasmic interaction between PINK1 and FBW7β in mammalian cells. FBW7β, a component of the Skp1-Cullin-1-F-box protein (SCF) complex-type ubiquitin ligase, is instrumental in recognizing substrates. Our findings demonstrate that FBW7β regulates PINK1 stability through the SCF complex and the proteasome pathway. It facilitates the K48-linked polyubiquitination of PINK1, marking it for degradation. When FBW7 is absent, PINK1 accumulates, leading to heightened mitophagy triggered by carbonyl cyanide 3-chlorophenylhydrazone treatment. Moreover, exposure to the toxic compound staurosporine accelerates PINK1 degradation via FBW7β, correlating with increased cell death. This study unravels the intricate mechanisms controlling PINK1 protein stability and sheds light on the novel role of FBW7β. These findings deepen our understanding of PINK1-related pathologies and potentially pave the way for therapeutic interventions.

Keywords:  FBW7; Neurodegenerative diseases; PINK1; Parkinson's disease; Proteasomal degradation; SCF complex; Ubiquitination

DOI:  https://doi.org/10.1016/j.jbc.2024.107198
Mol Cell. 2024 Mar 21. pii: S1097-2765(24)00168-0. [Epub ahead of print]84(6): 995-997

Integrating the response to stressed mitochondria.

Elliot Dine, Richard J Youle.

Chakrabarty et al.1 demonstrate that phospho-EIF2α (pEIF2α), the translation initiation factor that mediates the integrated stress response (ISR), is necessary and sufficient for the autophagic degradation of mitochondria following the addition of mitochondrial stressors.

DOI: https://doi.org/10.1016/j.molcel.2024.02.026
Nat Metab. 2024 Mar 19.

AMPK and insulin control the switch between mitochondrial hitchhiking of Pink1 mRNA and mitophagy in neurons.

DOI: https://doi.org/10.1038/s42255-024-01006-x
Cell Death Discov. 2024 Mar 21. 10(1): 149

miR-218-5p and doxorubicin combination enhances anticancer activity in breast cancer cells through Parkin-dependent mitophagy inhibition.

Francesco Davide Naso, Krenare Bruqi, Valeria Manzini, Valerio Chiurchiù, Mara D'Onofrio, Ivan Arisi, Flavie Strappazzon.

Breast Cancer (BC) is one of the most common tumours, and is known for its ability to develop resistance to chemotherapeutic treatments. Autophagy has been linked to chemotherapeutic response in several types of cancer, highlighting its contribution to this process. However, the role of mitophagy, a selective form of autophagy responsible for damaged mitochondria degradation, in the response to therapies in BC is still unclear. In order to address this point, we analysed the role of mitophagy in the treatment of the most common anticancer drug, doxorubicin (DXR), in different models of BC, such as a luminal A subtype-BC cell line MCF7 cells, cultured in 2-Dimension (2D) or in 3-Dimension (3D), and the triple negative BC (TNBC) cell line MDA-MB-231. Through a microarray analysis, we identified a relationship between mitophagy gene expressions related to the canonical PINK1/Parkin-mediated pathway and DXR treatment in BC cells. Afterwards, we demonstrated that the PINK1/Parkin-dependent mitophagy is indeed induced following DXR treatment and that exogenous expression of a small non-coding RNA, the miRNA-218-5p, known to target mRNA of Parkin, was sufficient to inhibit the DXR-mediated mitophagy in MCF7 and in MDA-MB-231 cells, thereby increasing their sensitivity to DXR. Considering the current challenges involved in BC refractory to treatment, our work could provide a promising approach to prevent tumour resistance and recurrence, potentially leading to the development of an innovative approach to combine mitophagy inhibition and chemotherapy.

DOI: https://doi.org/10.1038/s41420-024-01914-7
Neuropharmacology. 2024 Mar 15. pii: S0028-3908(24)00078-9. [Epub ahead of print] 109909

Neuro-modulatory impact of felodipine against experimentally-induced Parkinson's disease: Possible contribution of PINK1-Parkin mitophagy pathway.

Hadeer O Abou-Hany, Mohamed El-Sherbiny, Sally Elshaer, Eman Said, Tarek Moustafa.

  Parkinson's disease (PD) is a prevalent neurodegenerative disorder, characterized by motor and psychological dysfunction. Palliative treatment and dopamine replenishment therapy are the only available therapeutic options. Calcium channel blockers (CCBs) have been reported to protect against several neurodegenerative disorders. The current study was designed to evaluate the neuroprotective impact of Felodipine (10 mg/kg, orally) as a CCB on motor and biochemical dysfunction associated with experimentally induced PD using rotenone (2.5 mg/kg, IP) and to investigate the underlying mechanisms. Rotenone induced deleterious neuromotor outcomes, typical of those associated with PD. The striatum revealed increased oxidative burden and NO levels with decreased antioxidant capacity. Nrf2 content significantly decreased with the accumulation of α-synuclein and tau proteins in both the substantia nigra and striatum. These observations significantly improved with felodipine treatment. Of note, felodipine increased dopamine levels in the substantia nigra and striatum as confirmed by the suppression of inflammation and the significant reduction in striatal NF-κB and TNF-α contents. Moreover, felodipine enhanced mitophagy, as confirmed by a significant increase in mitochondrial Parkin and suppression of LC3a/b and SQSTM1/p62. In conclusion, felodipine restored dopamine synthesis, attenuated oxidative stress, inflammation, and mitochondrial dysfunction, and improved the mitophagy process resulting in improved PD-associated motor impairment.

Keywords:  Felodipine; LC3a/b; Mitophagy; Parkin; Parkinson's; SQSTM1/p62

DOI:  https://doi.org/10.1016/j.neuropharm.2024.109909
Mitochondrion. 2024 Mar 19. pii: S1567-7249(24)00032-1. [Epub ahead of print] 101874

Interplay of mitochondria associated membrane proteins and autophagy: Implications in neurodegeneration.

Prakash G Kulkarni, Vaibhavi M Mohire, Pranjal P Waghmare, Tanushree Banerjee.

  Since the discovery of membrane contact sites between ER and mitochondria called mitochondria-associated membranes (MAMs), several pieces of evidence identified their role in the regulation of different cellular processes such as Ca2+ signalling, mitochondrial transport, and dynamics, ER stress, inflammation, glucose homeostasis, and autophagy. The integrity of these membranes was found to be essential for the maintenance of these cellular functions. Accumulating pieces of evidence suggest that MAMs serve as a platform for autophagosome formation. However, the alteration within MAMs' structure is associated with the progression of neurodegenerative diseases. Dysregulated autophagy is a hallmark of neurodegeneration. Here, in this review, we highlight the present knowledge on MAMs, their structural composition, and their roles in different cellular functions. We also discuss the association of MAMs proteins with impaired autophagy and their involvement in the progression of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

Keywords:  Alzheimer’s disease (AD); Autophagy; Mitochondrial associated membranes (MAMs); Mitophagy; Parkinson’s disease (PD)

DOI:  https://doi.org/10.1016/j.mito.2024.101874