bims-tofagi 2024-10-13 papers

Sci Signal. 2024 10 08. 17(857): eadn5805

Siah3 acts as a physiological mitophagy suppressor that facilitates axonal degeneration.

Omer Abraham, Shifra Ben-Dor, Inna Goliand, Rebecca Haffner-Krausz, Sarah Phoebeluc Colaiuta, Andrew Kovalenko, Avraham Yaron.

Mitophagy eliminates dysfunctional mitochondria, and defects in this cellular housekeeping mechanism are implicated in various age-related diseases. Here, we found that mitophagy suppression by the protein Siah3 promoted developmental axonal remodeling in mice. Siah3-deficient mice displayed increased peripheral sensory innervation. Cultured Siah3-deficient sensory neurons exhibited delays in both axonal degeneration and caspase-3 activation in response to withdrawal of nerve growth factor. Mechanistically, Siah3 was transcriptionally induced by the loss of trophic support and formed a complex with the cytosolic E3 ubiquitin ligase parkin, a core component of mitophagy, in transfected cells. Axons of Siah3-deficient neurons mounted profound mitophagy upon initiation of degeneration but not under basal conditions. Neurons lacking both Siah3 and parkin did not exhibit the delay in trophic deprivation-induced axonal degeneration or the induction of axonal mitophagy that was seen in Siah3-deficient neurons. Our findings reveal that mitophagy regulation acts as a gatekeeper of a physiological axon elimination program.

DOI: https://doi.org/10.1126/scisignal.adn5805

Biochem Soc Trans. 2024 Oct 08. pii: BST20221364. [Epub ahead of print]

Coordinating BNIP3/NIX-mediated mitophagy in space and time.

Natalie M Niemi, Jonathan R Friedman.

Mitochondria maintain organellar homeostasis through multiple quality control pathways, including the clearance of defective or unwanted mitochondria by selective autophagy. This removal of mitochondria, mitophagy, is controlled in large part by the outer mitochondrial membrane mitophagy receptors BNIP3 and NIX. While it has long been appreciated that BNIP3 and NIX mediate mitophagy by controlling the recruitment of autophagic machinery to the mitochondrial surface, the requirement for the carefully controlled spatiotemporal regulation of receptor-mediated mitophagy has only recently come to light. Several new factors that regulate the BNIP3/NIX-mediated mitophagy pathway have emerged, and various loss-of-function cell and animal models have revealed the dire consequences of their dysregulation. In this mini-review, we discuss new insights into the mechanisms and roles of the regulation of BNIP3 and NIX and highlight questions that have emerged from the identification of these new regulators.

Keywords: autophagy; mitochondria; mitophagy

DOI: https://doi.org/10.1042/BST20221364

Sci Signal. 2024 10 08. 17(857): eads1228

A Siah3 of relief: A role for mitophagy as a fail-safe during developmental axon pruning.

Rina L Davidson, David J Simon.

Developmental axon pruning is controlled by a careful balance of pro- and anti-apoptotic signals, which are activated in response to external cues to sculpt mature neuronal circuitry. In this issue of Science Signaling, Abraham et al. define a safeguard against apoptotic axon pruning and illustrate that Siah3 represses Parkin-mediated mitophagy to control the availability of axonal mitochondria that activate the pruning process.

DOI: https://doi.org/10.1126/scisignal.ads1228

Structure. 2024 Sep 26. pii: S0969-2126(24)00381-2. [Epub ahead of print]

Mechanism of phospho-Ubls' specificity and conformational changes that regulate Parkin activity.

Dipti Ranjan Lenka, Shradha Chaurasiya, Loknath Ratnakar, Atul Kumar.

PINK1 and Parkin mutations lead to the early onset of Parkinson's disease. PINK1-mediated phosphorylation of ubiquitin (Ub), ubiquitin-like protein (NEDD8), and ubiquitin-like (Ubl) domain of Parkin activate autoinhibited Parkin E3 ligase. The mechanism of various phospho-Ubls' specificity and conformational changes leading to Parkin activation remain elusive. Herein, we show that compared to Ub, NEDD8 is a more robust binder and activator of Parkin. Structures and biophysical/biochemical data reveal specific recognition and underlying mechanisms of pUb/pNEDD8 and pUbl domain binding to the RING1 and RING0 domains, respectively. Also, pUb/pNEDD8 binding in the RING1 pocket promotes allosteric conformational changes in Parkin's catalytic domain (RING2), leading to Parkin activation. Furthermore, Parkinson's disease mutation K211N in the RING0 domain was believed to perturb Parkin activation due to loss of pUb binding. However, our data reveal allosteric conformational changes due to N211 that lock RING2 with RING0 to inhibit Parkin activity without disrupting pNEDD8/pUb binding.

Keywords: NEDD8; PINK1; Parkin; Parkinson's disease; RBR E3 ligase; X-ray crystallography; ubiquitin

DOI: https://doi.org/10.1016/j.str.2024.09.012