Редактирование: DNM1L (раздел)

==Publications==

{{medline-entry
|title=Aberrant mitochondrial morphology and function associated with impaired mitophagy and [[DNM1L]]-MAPK/ERK signaling are found in aged mutant Parkinsonian [[LRRK2]]  mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33300446
|abstract=Mitochondrial dysfunction causes energy deficiency and nigrostriatal neurodegeneration which is integral to the pathogenesis of Parkinson disease (PD). Clearance of defective mitochondria involves fission and ubiquitin-dependent degradation via mitophagy to maintain energy homeostasis. We hypothesize that [[LRRK2]] (leucine-rich repeat kinase 2) mutation disrupts mitochondrial turnover causing accumulation of defective mitochondria in aging brain. We found more ubiquitinated mitochondria with aberrant morphology associated with impaired function in aged (but not young) [[LRRK2]]  knockin mutant mouse striatum compared to wild-type (WT) controls. [[LRRK2]]  mutant mouse embryonic fibroblasts (MEFs) exhibited reduced MAP1LC3/LC3 activation indicating impaired macroautophagy/autophagy. Mutant MEFs under FCCP-induced (mitochondrial uncoupler) stress showed increased LC3-aggregates demonstrating impaired mitophagy. Using a novel flow cytometry assay to quantify mitophagic rates in MEFs expressing photoactivatable [i]mito[/i]-PAmCherry, we found significantly slower mitochondria clearance in mutant cells. Specific [[LRRK2]] kinase inhibition using [[GNE]]-7915 did not alleviate impaired mitochondrial clearance suggesting a lack of direct relationship to increased kinase activity alone. [[DNM1L]]/Drp1 knockdown in MEFs slowed mitochondrial clearance indicating that [[DNM1L]] is a prerequisite for mitophagy. [[DNM1L]] knockdown in slowing mitochondrial clearance was less pronounced in mutant MEFs, indicating preexisting impaired [[DNM1L]] activation. [[DNM1L]] knockdown disrupted mitochondrial network which was more evident in mutant MEFs. [[DNM1L]]-Ser616 and MAPK/ERK phosphorylation which mediate mitochondrial fission and downstream mitophagic processes was apparent in WT using FCCP-induced stress but not mutant MEFs, despite similar total MAPK/ERK and [[DNM1L]] levels. In conclusion, aberrant mitochondria morphology and dysfunction associated with impaired mitophagy and [[DNM1L]]-MAPK/ERK signaling are found in mutant [[LRRK2]] MEFs and mouse brain.   ATP: adenosine triphosphate; BAX: [[BCL2]]-associated X protein; CDK1: cyclin-dependent kinase 1; CDK5: cyclin-dependent kinase 5; CQ: chloroquine; CSF: cerebrospinal fluid; [[DNM1L]]/DRP1: dynamin 1-like; ELISA: enzyme-linked immunosorbent assay; FACS: fluorescence-activated cell sorting; FCCP: carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; LAMP2A: lysosomal-associated membrane protein 2A; [[LRRK2]]: leucine-rich repeat kinase 2; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK1/ERK2: mitogen-activated protein kinase 1; MEF: mouse embryonic fibroblast; MFN1: mitofusin 1; MMP: mitochondrial membrane potential; PAmCherry: photoactivatable-mCherry; PD: Parkinson disease; PINK1: [[PTEN]] induced putative kinase 1; PRKN/PARKIN: parkin RBR E3 ubiquitin protein ligase; [[RAB10]]: [[RAB10]], member RAS oncogene family; RAF: v-raf-leukemia oncogene; SNCA: synuclein, alpha; TEM: transmission electron microscopy; VDAC: voltage-dependent anion channel; WT: wild type; SQSTM1/p62: sequestosome 1.

|keywords=* Aging
* Dnm1l/DRP1
* SQSTM1/p62
* knockin mice
* macroautophagy
* mitochondria dysfunction
* mitochondrial fission
* mitophagy
* parkinson disease
* ubiquitination
|full-text-url=https://sci-hub.do/10.1080/15548627.2020.1850008
}}