bims-mitlys 2021-03-14 papers

Issue of 2021‒03‒14
four papers selected by
Nicoletta Plotegher
University of Padua

Mol Neurodegener. 2021 03 08. 16(1): 15

Cholesterol alters mitophagy by impairing optineurin recruitment and lysosomal clearance in Alzheimer's disease.

Vicente Roca-Agujetas, Elisabet Barbero-Camps, Cristina de Dios, Petar Podlesniy, Xenia Abadin, Albert Morales, Montserrat Marí, Ramon Trullàs, Anna Colell.

BACKGROUND: Emerging evidence indicates that impaired mitophagy-mediated clearance of defective mitochondria is a critical event in Alzheimer's disease (AD) pathogenesis. Amyloid-beta (Aβ) metabolism and the microtubule-associated protein tau have been reported to regulate key components of the mitophagy machinery. However, the mechanisms that lead to mitophagy dysfunction in AD are not fully deciphered. We have previously shown that intraneuronal cholesterol accumulation can disrupt the autophagy flux, resulting in low Aβ clearance. In this study, we examine the impact of neuronal cholesterol changes on mitochondrial removal by autophagy.METHODS: Regulation of PINK1-parkin-mediated mitophagy was investigated in conditions of acute (in vitro) and chronic (in vivo) high cholesterol loading using cholesterol-enriched SH-SY5Y cells, cultured primary neurons from transgenic mice overexpressing active SREBF2 (sterol regulatory element binding factor 2), and mice of increasing age that express the amyloid precursor protein with the familial Alzheimer Swedish mutation (Mo/HuAPP695swe) and mutant presenilin 1 (PS1-dE9) together with active SREBF2.
RESULTS: In cholesterol-enriched SH-SY5Y cells and cultured primary neurons, high intracellular cholesterol levels stimulated mitochondrial PINK1 accumulation and mitophagosomes formation triggered by Aβ while impairing lysosomal-mediated clearance. Antioxidant recovery of cholesterol-induced mitochondrial glutathione (GSH) depletion prevented mitophagosomes formation indicating mitochondrial ROS involvement. Interestingly, when brain cholesterol accumulated chronically in aged APP-PSEN1-SREBF2 mice the mitophagy flux was affected at the early steps of the pathway, with defective recruitment of the key autophagy receptor optineurin (OPTN). Sustained cholesterol-induced alterations in APP-PSEN1-SREBF2 mice promoted an age-dependent accumulation of OPTN into HDAC6-positive aggresomes, which disappeared after in vivo treatment with GSH ethyl ester (GSHee). The analyses in post-mortem brain tissues from individuals with AD confirmed these findings, showing OPTN in aggresome-like structures that correlated with high mitochondrial cholesterol levels in late AD stages.
CONCLUSIONS: Our data demonstrate that accumulation of intracellular cholesterol reduces the clearance of defective mitochondria and suggest recovery of the cholesterol homeostasis and the mitochondrial scavenging of ROS as potential therapeutic targets for AD.

Keywords: APP-PSEN1 mice; Aggressomes; Glutathione; Mitochondria; Optineurin; Oxidative stress; PINK1; Parkin

DOI: https://doi.org/10.1186/s13024-021-00435-6

Dev Cell. 2021 Mar 02. pii: S1534-5807(21)00121-0. [Epub ahead of print]

Autophagy and organelle homeostasis in cancer.

Dannah R Miller, Andrew Thorburn.

Beginning with the earliest studies of autophagy in cancer, there have been indications that autophagy can both promote and inhibit cancer growth and progression; autophagy regulation of organelle homeostasis is similarly complicated. In this review we discuss pro- and antitumor effects of organelle-targeted autophagy and how this contributes to several hallmarks of cancer, such as evading cell death, genomic instability, and altered metabolism. Typically, the removal of damaged or dysfunctional organelles prevents tumor development but can also aid in proliferation or drug resistance in established tumors. By better understanding how organelle-specific autophagy takes place and can be manipulated, it may be possible to go beyond the brute-force approach of trying to manipulate all autophagy in order to improve therapeutic targeting of this process in cancer.

Keywords: ER-phagy; autophagy; cancer; lysophagy; mitophagy

DOI: https://doi.org/10.1016/j.devcel.2021.02.010

Autophagy. 2021 Mar 08. 1-10

Mt-Keima detects PINK1-PRKN mitophagy in vivo with greater sensitivity than mito-QC.

Yi-Ting Liu, Danielle A Sliter, Mario K Shammas, Xiaoping Huang, Chunxin Wang, Hannah Calvelli, Dragan S Maric, Derek P Narendra.

PINK1 and PRKN, which cause Parkinson disease when mutated, form a quality control mitophagy pathway that is well-characterized in cultured cells. The extent to which the PINK1-PRKN pathway contributes to mitophagy in vivo, however, is controversial. This is due in large part to conflicting results from studies using one of two mitophagy reporters: mt-Keima or mito-QC. Studies using mt-Keima have generally detected PINK1-PRKN mitophagy in vivo, whereas those using mito-QC generally have not. Here, we directly compared the performance of mito-QC and mt-Keima in cell culture and in mice subjected to a PINK1-PRKN activating stress. We found that mito-QC was less sensitive than mt-Keima for mitophagy, and that this difference was more pronounced for PINK1-PRKN mitophagy. These findings suggest that mito-QC's poor sensitivity may account for conflicting reports of PINK1-PRKN mitophagy in vivo and caution against using mito-QC as a reporter for PINK1-PRKN mitophagy.

Keywords: Autophagy; PARK2; PARKIN; Parkinson; degradation; disease; mitochondria; neurodegeneration; organelle

DOI: https://doi.org/10.1080/15548627.2021.1896924