bims-tofagi 2024-01-21 papers

on Mitophagy

Issue of 2024–01–21
seven papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea

Activation of Ca2+ phosphatase Calcineurin regulates Parkin translocation to mitochondria and mitophagy in flies.
Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models.
Interaction of PINK1 with nucleotides and kinetin.
USP30 inhibition induces mitophagy and reduces oxidative stress in parkin-deficient human neurons.
Mitophagy in hypertension-mediated organ damage.
G-quadruplex in mitochondria as a possible biomarker for mitophagy detection.
Correction: Cisplatin resistance can be curtailed by blunting Bnip3-mediated mitochondrial autophagy.

Cell Death Differ. 2024 Jan 18.

Activation of Ca2+ phosphatase Calcineurin regulates Parkin translocation to mitochondria and mitophagy in flies.

Elena Marchesan, Alice Nardin, Sofia Mauri, Greta Bernardo, Vivek Chander, Simone Di Paola, Monica Chinellato, Sophia von Stockum, Joy Chakraborty, Stephanie Herkenne, Valentina Basso, Emilie Schrepfer, Oriano Marin, Laura Cendron, Diego L Medina, Luca Scorrano, Elena Ziviani.

Selective removal of dysfunctional mitochondria via autophagy is crucial for the maintenance of cellular homeostasis. This event is initiated by the translocation of the E3 ubiquitin ligase Parkin to damaged mitochondria, and it requires the Serine/Threonine-protein kinase PINK1. In a coordinated set of events, PINK1 operates upstream of Parkin in a linear pathway that leads to the phosphorylation of Parkin, Ubiquitin, and Parkin mitochondrial substrates, to promote ubiquitination of outer mitochondrial membrane proteins. Ubiquitin-decorated mitochondria are selectively recruiting autophagy receptors, which are required to terminate the organelle via autophagy. In this work, we show a previously uncharacterized molecular pathway that correlates the activation of the Ca2+-dependent phosphatase Calcineurin to Parkin translocation and Parkin-dependent mitophagy. Calcineurin downregulation or genetic inhibition prevents Parkin translocation to CCCP-treated mitochondria and impairs stress-induced mitophagy, whereas Calcineurin activation promotes Parkin mitochondrial recruitment and basal mitophagy. Calcineurin interacts with Parkin, and promotes Parkin translocation in the absence of PINK1, but requires PINK1 expression to execute mitophagy in MEF cells. Genetic activation of Calcineurin in vivo boosts basal mitophagy in neurons and corrects locomotor dysfunction and mitochondrial respiratory defects of a Drosophila model of impaired mitochondrial functions. Our study identifies Calcineurin as a novel key player in the regulation of Parkin translocation and mitophagy.

DOI: https://doi.org/10.1038/s41418-023-01251-9
Cell Rep. 2024 Jan 17. pii: S2211-1247(24)00009-3. [Epub ahead of print]43(2): 113681

Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models.

Madeleine J Twyning, Roberta Tufi, Thomas P Gleeson, Kinga M Kolodziej, Susanna Campesan, Ana Terriente-Felix, Lewis Collins, Federica De Lazzari, Flaviano Giorgini, Alexander J Whitworth.

  Mitochondrial calcium (Ca2+) uptake augments metabolic processes and buffers cytosolic Ca2+ levels; however, excessive mitochondrial Ca2+ can cause cell death. Disrupted mitochondrial function and Ca2+ homeostasis are linked to numerous neurodegenerative diseases (NDs), but the impact of mitochondrial Ca2+ disruption is not well understood. Here, we show that Drosophila models of multiple NDs (Parkinson's, Huntington's, Alzheimer's, and frontotemporal dementia) reveal a consistent increase in neuronal mitochondrial Ca2+ levels, as well as reduced mitochondrial Ca2+ buffering capacity, associated with increased mitochondria-endoplasmic reticulum contact sites (MERCs). Importantly, loss of the mitochondrial Ca2+ uptake channel MCU or overexpression of the efflux channel NCLX robustly suppresses key pathological phenotypes across these ND models. Thus, mitochondrial Ca2+ imbalance is a common feature of diverse NDs in vivo and is an important contributor to the disease pathogenesis. The broad beneficial effects from partial loss of MCU across these models presents a common, druggable target for therapeutic intervention.

Keywords:  Alzheimer's disease; CP: Neuroscience; Drosophila; Huntington's disease; MCU; NCLX; Parkinson's disease; calcium overload; frontotemporal dementia; mitochondrial calcium; neurodegeneration

DOI:  https://doi.org/10.1016/j.celrep.2024.113681
Sci Adv. 2024 Jan 19. 10(3): eadj7408

Interaction of PINK1 with nucleotides and kinetin.

Zhong Yan Gan, Sylvie Callegari, Thanh N Nguyen, Nicholas S Kirk, Andrew Leis, Michael Lazarou, Grant Dewson, David Komander.

The ubiquitin kinase PINK1 accumulates on damaged mitochondria to trigger mitophagy, and PINK1 loss-of-function mutations cause early onset Parkinson's disease. Nucleotide analogs such as kinetin triphosphate (KTP) were reported to enhance PINK1 activity and may represent a therapeutic strategy for the treatment of Parkinson's disease. Here, we investigate the interaction of PINK1 with nucleotides, including KTP. We establish a cryo-EM platform exploiting the dodecamer assembly of Pediculus humanus corporis (Ph) PINK1 and determine PINK1 structures bound to AMP-PNP and ADP, revealing conformational changes in the kinase N-lobe that help establish PINK1's ubiquitin binding site. Notably, we find that KTP is unable to bind PhPINK1 or human (Hs) PINK1 due to a steric clash with the kinase "gatekeeper" methionine residue, and mutation to Ala or Gly is required for PINK1 to bind and use KTP as a phosphate donor in ubiquitin phosphorylation and mitophagy. HsPINK1 M318G can be used to conditionally uncouple PINK1 stabilization and activity on mitochondria.

DOI: https://doi.org/10.1126/sciadv.adj7408
Cell Death Dis. 2024 Jan 15. 15(1): 52

USP30 inhibition induces mitophagy and reduces oxidative stress in parkin-deficient human neurons.

Justyna Okarmus, Jette Bach Agergaard, Tina C Stummann, Henriette Haukedal, Malene Ambjørn, Kristine K Freude, Karina Fog, Morten Meyer.

Ubiquitination of mitochondrial proteins plays an important role in the cellular regulation of mitophagy. The E3 ubiquitin ligase parkin (encoded by PARK2) and the ubiquitin-specific protease 30 (USP30) have both been reported to regulate the ubiquitination of outer mitochondrial proteins and thereby mitophagy. Loss of E3 ligase activity is thought to be pathogenic in both sporadic and inherited Parkinson's disease (PD), with loss-of-function mutations in PARK2 being the most frequent cause of autosomal recessive PD. The aim of the present study was to evaluate whether mitophagy induced by USP30 inhibition provides a functional rescue in isogenic human induced pluripotent stem cell-derived dopaminergic neurons with and without PARK2 knockout (KO). Our data show that healthy neurons responded to CCCP-induced mitochondrial damage by clearing the impaired mitochondria and that this process was accelerated by USP30 inhibition. Parkin-deficient neurons showed an impaired mitophagic response to the CCCP challenge, although mitochondrial ubiquitination was enhanced. USP30 inhibition promoted mitophagy in PARK2 KO neurons, independently of whether left in basal conditions or treated with CCCP. In PARK2 KO, as in control neurons, USP30 inhibition balanced oxidative stress levels by reducing excessive production of reactive oxygen species. Interestingly, non-dopaminergic neurons were the main driver of the beneficial effects of USP30 inhibition. Our findings demonstrate that USP30 inhibition is a promising approach to boost mitophagy and improve cellular health, also in parkin-deficient cells, and support the potential relevance of USP30 inhibitors as a novel therapeutic approach in diseases with a need to combat neuronal stress mediated by impaired mitochondria.

DOI: https://doi.org/10.1038/s41419-024-06439-6
Front Cardiovasc Med. 2023 ;10 1309863

Mitophagy in hypertension-mediated organ damage.

Yulong Ma, Xunjie Zhou, Mingtai Gui, Lei Yao, Jianhua Li, Xiaozhe Chen, Mingzhu Wang, Bo Lu, Deyu Fu.

  Hypertension constitutes a pervasive chronic ailment on a global scale, frequently inflicting damage upon vital organs, such as the heart, blood vessels, kidneys, brain, and others. And this is a complex clinical dilemma that requires immediate attention. The mitochondria assume a crucial function in the generation of energy, and it is of utmost importance to eliminate any malfunctioning or surplus mitochondria to uphold intracellular homeostasis. Mitophagy is considered a classic example of selective autophagy, an important component of mitochondrial quality control, and is closely associated with many physiological and pathological processes. The ubiquitin-dependent pathway, facilitated by PINK1/Parkin, along with the ubiquitin-independent pathway, orchestrated by receptor proteins such as BNIP3, NIX, and FUNDC1, represent the extensively investigated mechanisms underlying mitophagy. In recent years, research has increasingly shown that mitophagy plays an important role in organ damage associated with hypertension. Exploring the molecular mechanisms of mitophagy in hypertension-mediated organ damage could represent a critical avenue for future research in the development of innovative therapeutic modalities. Therefore, this article provides a comprehensive review of the impact of mitophagy on organ damage due to hypertension.

Keywords:  hypertension; mitochondria; mitochondrial quality control; mitophagy; organ damage

DOI:  https://doi.org/10.3389/fcvm.2023.1309863
Int J Biol Macromol. 2024 Jan 11. pii: S0141-8130(24)00140-5. [Epub ahead of print]259(Pt 2): 129337

G-quadruplex in mitochondria as a possible biomarker for mitophagy detection.

Boyang Zhang, Ranran Sun, Ruiyang Bai, Zhicheng Sun, Ruping Liu, Wenchao Li, Li Yao, Hongxia Sun, Yalin Tang.

  Mitochondrial autophagy (mitophagy) is a key physiological process that maintains the homeostasis of mitochondrial quality and quantity. Monitoring mitophagy is of great significance for detecting cellular abnormalities and developing therapeutic drugs. However, there are still very few biomarkers specifically developed for monitoring mitophagy. Here, we propose for the first time that mitochondrial G-quadruplex may serve as a biomarker for mitophagy detection, and develope a fluorescent light-up probe AMTC to monitor mitophagy in live cells. During mitophagy, AMTC fluorescence is significantly enhanced, but once mitophagy is inhibited, its fluorescence immediately decreases. The fluorescence behavior of AMTC implicates an increase in the formation of mitochondrial G-quadruplex during mitophagy. This inference has also been supported by the other two G-quadruplex probes. Taken together, this work provides a new possible biomarker and detection tool for the study of mitophagy.

Keywords:  Biomarker; Mitochondrial G-quadruplex; Mitophagy monitoring

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.129337
Cell Death Dis. 2024 Jan 18. 15(1): 68

Correction: Cisplatin resistance can be curtailed by blunting Bnip3-mediated mitochondrial autophagy.

Caterina Vianello, Veronica Cocetta, Daniela Catanzaro, Gerald W Dorn, Angelo De Milito, Flavio Rizzolio, Vincenzo Canzonieri, Erika Cecchin, Rossana Roncato, Giuseppe Toffoli, Vincenzo Quagliariello, Annabella Di Mauro, Simona Losito, Nicola Maurea, Cono Scaffa, Gabriele Sales, Luca Scorrano, Marta Giacomello, Monica Montopoli.

DOI: https://doi.org/10.1038/s41419-023-06402-x