bims-tofagi 2024-02-25 papers

Cell Death Discov. 2024 Feb 19. 10(1): 88

Mechanism and role of mitophagy in the development of severe infection.

Mitochondria produce adenosine triphosphate and potentially contribute to proinflammatory responses and cell death. Mitophagy, as a conservative phenomenon, scavenges waste mitochondria and their components in the cell. Recent studies suggest that severe infections develop alongside mitochondrial dysfunction and mitophagy abnormalities. Restoring mitophagy protects against excessive inflammation and multiple organ failure in sepsis. Here, we review the normal mitophagy process, its interaction with invading microorganisms and the immune system, and summarize the mechanism of mitophagy dysfunction during severe infection. We highlight critical role of normal mitophagy in preventing severe infection.

DOI: https://doi.org/10.1038/s41420-024-01844-4

Cell Death Differ. 2024 Feb 23.

Exposure of the inner mitochondrial membrane triggers apoptotic mitophagy.

Tahnee L Saunders, Simon P Windley, Gediminas Gervinskas, Katherine R Balka, Caitlin Rowe, Rachael Lane, Maximilien Tailler, Thanh Ngoc Nguyen, Georg Ramm, Michael Lazarou, Dominic De Nardo, Benjamin T Kile, Kate McArthur.

During apoptosis mediated by the intrinsic pathway, BAX/BAK triggers mitochondrial permeabilization and the release of cytochrome-c, followed by a dramatic remodelling of the mitochondrial network that results in mitochondrial herniation and the subsequent release of pro-inflammatory mitochondrial components. Here, we show that mitochondrial herniation and subsequent exposure of the inner mitochondrial membrane (IMM) to the cytoplasm, initiates a unique form of mitophagy to deliver these damaged organelles to lysosomes. IMM-induced mitophagy occurs independently of canonical PINK1/Parkin signalling and is driven by ubiquitination of the IMM. Our data suggest IMM-induced mitophagy is an additional safety mechanism that cells can deploy to contain damaged mitochondria. It may have particular relevance in situations where caspase activation is incomplete or inhibited, and in contexts where PINK1/Parkin-mitophagy is impaired or overwhelmed.

DOI: https://doi.org/10.1038/s41418-024-01260-2

Cell Rep Methods. 2024 Feb 13. pii: S2667-2375(24)00027-4. [Epub ahead of print] 100712

Design and high-throughput implementation of MALDI-TOF/MS-based assays for Parkin E3 ligase activity.

Ryan Traynor, Jennifer Moran, Michael Stevens, Odetta Antico, Axel Knebel, Bahareh Behrouz, Kalpana Merchant, C James Hastie, Paul Davies, Miratul M K Muqit, Virginia De Cesare.

Parkinson's disease (PD) is a progressive neurological disorder that manifests clinically as alterations in movement as well as multiple non-motor symptoms including but not limited to cognitive and autonomic abnormalities. Loss-of-function mutations in the gene encoding the ubiquitin E3 ligase Parkin are causal for familial and juvenile PD. Among several therapeutic approaches being explored to treat or improve the prognosis of patients with PD, the use of small molecules able to reinstate or boost Parkin activity represents a potential pharmacological treatment strategy. A major barrier is the lack of high-throughput platforms for the robust and accurate quantification of Parkin activity in vitro. Here, we present two different and complementary Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF/MS)-based approaches for the quantification of Parkin E3 ligase activity in vitro. Both approaches are scalable for high-throughput primary screening to facilitate the identification of Parkin modulators.

Keywords: CP: Molecular biology; CP: Neuroscience; MALDI-TOF/MS; PINK1/Parkin pathway; Parkin E3 ligase; Parkinson's disease; drug discovery; high-throughput screening; ubiquitin

DOI: https://doi.org/10.1016/j.crmeth.2024.100712