bims-midbra 2022-03-13 papers

Issue of 2022‒03‒13
four papers selected by
Ana Paula Mendonça
University of Padova

Biogerontology. 2022 Mar 09.

Alterations in hippocampal mitochondrial dynamics are associated with neurodegeneration and recognition memory decline in old male mice.

Ela Mishra, Mahendra Kumar Thakur.

Mitochondrial dynamics is a key process that modulates the ultrastructure, quality and function of mitochondria. It is disrupted in numerous major neurodegenerative disorders including Parkinson's, Alzheimer's and Huntington's disease. Mitochondrial dysfunction has been correlated with the loss of memory. Previous studies suggest the involvement of Vdac1 and Drp1 in outer mitochondrial membrane permeabilization and promotion of mitochondrial fragmentation through Drp1 phosphorylation at S616. However, alterations in mitochondrial dynamics with respect to aging, memory loss and neurodegeneration remain unexplored. Therefore, the present study focuses on the involvement of mitochondrial dynamics in neurodegeneration and recognition memory decline during aging. The recognition memory decline was validated by the novel object recognition test and measurement of hippocampal Arc protein level during aging. The ultrastructure analysis revealed a decline in mitochondrial length and area, while an increase in the number of fragmented, round and disrupted mitochondria in the hippocampus during aging. Disruption was also evident in mitochondrial cristae and membrane with advancing age. The change in mitochondrial morphology was corroborated by an increase in the expression of phospho-Drp1 (S616) and Cyt-c proteins but decline in Mfn2, LC3B, Vdac1, Bcl-XL and Bcl-2 proteins in the hippocampus during aging. Taken together, our findings reveal that an increase in the expression of phospho-Drp1 (S616) and decrease in Mfn2 and LC3B proteins in the hippocampus bring about a reduction in mitochondrial length and area, and rise in mitochondrial fragmentation leading to reduced neuronal cell density, increased neurodegeneration and recognition memory decline in old male mice. Diagram depicts the increase in hippocampal mitochondrial fragmentation during aging of mice. Increased mitochondrial fragmentation causes distorted mitochondrial function such as decrease in ATP/ADP transportation due to decrease in Vdac1 protein level and increase in oxidative damage. These alterations result in hippocampal neurodegeneration and consequently impairment in recognition memory during aging.

Keywords: Aging; Apoptosis; Hippocampus; Mitochondrial dynamics; Neurodegeneration; Recognition memory

DOI: https://doi.org/10.1007/s10522-022-09960-3

Mol Neurobiol. 2022 Mar 09.

Mitochondrial Quality and Quantity Control: Mitophagy Is a Potential Therapeutic Target for Ischemic Stroke.

Meiying Song, Yuan Zhou, Xiang Fan.

Ischemic stroke is a cerebrovascular disease with high mortality and disability, which seriously affects the health and lives of people around the world. Effective treatment for ischemic stroke has been limited by its complex pathological mechanisms. Increasing evidence has indicated that mitochondrial dysfunction plays an essential role in the occurrence, development, and pathological processes of ischemic stroke. Therefore, strict control of the quality and quantity of mitochondria via mitochondrial fission and fusion as well as mitophagy is beneficial to the survival and normal function maintenance of neurons. Under certain circumstances, excessive mitophagy also could induce cell death. This review discusses the dynamic changes and double-edged roles of mitochondria and related signaling pathways of mitophagy in the pathophysiology of ischemic stroke. Furthermore, we focus on the possibility of modulating mitophagy as a potential therapy for the prevention and prognosis of ischemic stroke. Notably, we reviewed recent advances in the studies of natural compounds, which could modulate mitophagy and exhibit neuroprotective effects, and discussed their potential application in the treatment of ischemic stroke.

Keywords: Ischemic stroke; Mitochondria; Mitochondrial dynamics; Mitophagy

DOI: https://doi.org/10.1007/s12035-022-02795-6

Food Funct. 2022 Mar 09.

Dioscin relieves diabetic nephropathy via suppressing oxidative stress and apoptosis, and improving mitochondrial quality and quantity control.

Yujie Zhong, Jiayu Liu, Dianjun Sun, Tianmin Guo, Yanpeng Yao, Xiaodong Xia, Chao Shi, Xiaoli Peng.

Dioscin is a steroidal saponin isolated from various kinds of vegetables and herbs and possesses various biological activities. In this study, the protective effect of dioscin on diabetic nephropathy (DN) was explored. Dioscin and metformin (positive control) were administered orally to diabetic rats daily for 8 weeks. The biochemistry parameters, pancreas and kidney histological changes, oxidative stress, inflammation, apoptosis, autophagy, and mitochondrial quality and quantity control (mitophagy and mitochondrial fission/fusion) were measured. Our results showed that dioscin effectively reduced blood glucose, pancreatic injury, renal function markers and renal pathological changes in DN rat kidneys. Dioscin reduced O2- and H2O2 levels, decreased MDA levels, enhanced antioxidant enzyme (SOD, CAT) activities, and reduced inflammatory factor expressions. Moreover, NOX4 expression and the disorder of the mitochondrial respiratory chain were reversed by dioscin. Furthermore, apoptosis mediated by the mitochondria and ER stress was inhibited by dioscin through downregulating the expressions of Bax, CytC, Apaf-1, caspase 9, p-PERK, p-EIF2α, IRE1, p-IRE1, XBP1s, ATF4, p-CHOP and caspase 12. In addition, autophagy was enhanced by dioscin via an AMPK-mTOR pathway. Mitophagy and mitochondrial fission/fusion belong to the mitochondrial quality and quantity control process, which was improved by dioscin via regulating Parkin, PINK1, DRP1, p-DRP1 and MFN2 expressions. Collectively, these results suggested that dioscin protected against DN through inhibiting oxidative stress, inflammation, and apoptosis mediated by the mitochondria and ER stress. Autophagy and mitochondrial quality and quantity control (mitophagy and mitochondrial fission/fusion) were also improved by dioscin.

DOI: https://doi.org/10.1039/d1fo02733f

Autophagy. 2022 Mar 11. 1-3

Iron chelation promotes mitophagy through SENP3-mediated deSUMOylation of FIS1.

Kevin A Wilkinson, Chun Guo.

The selective clearance of mitochondria by mitophagy is an important quality control mechanism for maintaining mitochondrial and cellular health. Iron chelation, for example by the compound deferiprone (DFP), leads to a specific form of PINK1-PRKN/Parkin-independent mitophagy; however, the molecular mechanisms underlying this are poorly understood. In our recent paper, we examined the role of the deSUMOylating enzyme SENP3 in DFP-induced mitophagy. We observed that SENP3 levels are enhanced by DFP treatment, and that SENP3 is essential for DFP-induced mitophagy. Furthermore, we identified the mitochondrial protein FIS1, which is also required for DFP-induced mitophagy, as a novel SUMO substrate. Our data demonstrate that SENP3-dependent deSUMOylation of FIS1 enhances FIS1 mitochondrial targeting, to promote mitophagy in response to DFP treatment. These findings offer new insight into the mechanisms underlying mitophagy upon iron chelation, and have relevance to the therapeutic potential of DFP in a number of disorders, including Parkinson disease. Abbreviations DFP: deferiprone; OMM: outer mitochondrial membrane. PD: Parkinson disease; SUMO: small ubiquitin like modifier.

Keywords: FIS1; SENP3; SUMO; iron chelation; mitophagy

DOI: https://doi.org/10.1080/15548627.2022.2046898