The pharmacological regulation of cellular mitophagy

Small molecules are pharmacological tools of considerable value for dissecting complex biological processes and identifying potential therapeutic interventions. Recently, the cellular quality-control process of mitophagy has attracted considerable research interest; however, the limited availability of suitable chemical probes has restricted our understanding of the molecular mechanisms involved. Current approaches to initiate mitophagy include acute dissipation of the mitochondrial membrane potential (ΔΨm) by mitochondrial uncouplers (for example, FCCP/CCCP) and the use of antimycin A and oligomycin to impair respiration. Both approaches impair mitochondrial homeostasis and therefore limit the scope for dissection of subtle, bioenergy-related regulatory phenomena. Recently, novel mitophagy activators acting independently of the respiration collapse have been reported, offering new opportunities to understand the process and potential for therapeutic exploitation. We have summarized the current status of mitophagy modulators and analyzed the available chemical tools, commenting on their advantages, limitations and current applications

Luminescence Dating in Fluvial Settings: Overcoming the Challenge of Partial Bleaching

Optically stimulated luminescence (OSL) dating is a versatile technique that utilises the two most ubiquitous minerals on Earth (quartz or K-feldspar) for constraining the timing of sediment deposition. It has provided accurate ages in agreement with independent age control in many fluvial settings, but is often characterised by partial bleaching of individual grains. Partial bleaching can occur where sunlight exposure is limited and so only a portion of the grains in the sample was exposed to sunlight prior to burial, especially in sediment-laden, turbulent or deep water columns. OSL analysis on multiple grains can provide accurate ages for partially bleached sediments where the OSL signal intensity is dominated by a single brighter grain, but will overestimate the age where the OSL signal intensity is equally as bright (often typical of K-feldspar) or as dim (sometimes typical of quartz). In such settings, it is important to identify partial bleaching and the minimum dose population, preferably by analysing single grains, and applying the appropriate statistical age model to the dose population obtained for each sample. To determine accurate OSL ages using these age models, it is important to quantify the amount of scatter (or overdispersion) in the well-bleached part of the partially bleached dose distribution, which can vary between sediment samples depending upon the bedrock sources and transport histories of grains. Here, we discuss how the effects of partial bleaching can be easily identified and overcome to determine accurate ages. This discussion will therefore focus entirely on the burial dose determination for OSL dating, rather than the dose-rate, as only the burial doses are impacted by the effects of partial bleaching

Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy

Despite their importance as signaling hubs, the function of mitochondria-ER contact sites in mitochondrial quality control pathways remains unexplored. Here we describe a mechanism by which Mfn2, a mitochondria-ER tether, gates the autophagic turnover of mitochondria by PINK1 and parkin. Mitochondria-ER appositions are destroyed during mitophagy, and reducing mitochondria-ER contacts increases the rate of mitochondrial degradation. Mechanistically, parkin/PINK1 catalyze a rapid burst of Mfn2 phosphoubiquitination to trigger p97-dependent disassembly of Mfn2 complexes from the outer mitochondrial membrane, dissociating mitochondria from the ER. We additionally demonstrate that a major portion of the facilitatory effect of p97 on mitophagy is epistatic to Mfn2 and promotes the availability of other parkin substrates such as VDAC1. Finally, we reconstitute the action of these factors on Mfn2 and VDAC1 ubiquitination in a cell-free assay. We show that mitochondria-ER tethering suppresses mitophagy and describe a parkin-/PINK1-dependent mechanism that regulates the destruction of mitochondria-ER contact sites