bims-mitpro 2023-08-13 papers

bims-mitpro

Biomed News

on Mitochondrial Proteostasis

Issue of 2023‒08‒13
nine papers selected by
Andreas Kohler

FBXL4 mutations cause excessive mitophagy via BNIP3/BNIP3L accumulation leading to mitochondrial DNA depletion syndrome.
Protein disorder in the regulatory control of mitophagy.
Parkinson's disease neurons exhibit alterations in mitochondrial quality control proteins.
ATAD3A: A Key Regulator of Mitochondria-Associated Diseases.
The role of mitochondria in myocardial damage caused by energy metabolism disorders: From mechanisms to therapeutics.
Caspase 3 exhibits a yeast metacaspase proteostasis function that protects mitochondria from toxic TDP43 aggregates.
Alterations in Mitochondrial Morphology and Quality Control in Primary Mouse Lung Microvascular Endothelial Cells and Human Dermal Fibroblasts under Hyperglycemic Conditions.
Knockdown of microRNA-96-5p resists oxidative stress-induced apoptosis in nucleus pulposus cells.
The Role of Mitophagy in Glaucomatous Neurodegeneration.

Cell Death Differ. 2023 Aug 11.

FBXL4 mutations cause excessive mitophagy via BNIP3/BNIP3L accumulation leading to mitochondrial DNA depletion syndrome.

Yingji Chen, Dongyue Jiao, Yang Liu, Xiayun Xu, Yilin Wang, Xiaona Luo, Hexige Saiyin, Yao Li, Kun Gao, Yucai Chen, Shi-Min Zhao, Lixiang Ma, Chenji Wang.

Mitochondria are essential organelles found in eukaryotic cells that play a crucial role in ATP production through oxidative phosphorylation (OXPHOS). Mitochondrial DNA depletion syndrome (MTDPS) is a group of genetic disorders characterized by the reduction of mtDNA copy number, leading to deficiencies in OXPHOS and mitochondrial functions. Mutations in FBXL4, a substrate-binding adaptor of Cullin 1-RING ubiquitin ligase complex (CRL1), are associated with MTDPS, type 13 (MTDPS13). Here, we demonstrate that, FBXL4 directly interacts with the mitophagy cargo receptors BNIP3 and BNIP3L, promoting their degradation through the ubiquitin-proteasome pathway via the assembly of an active CRL1FBXL4 complex. However, MTDPS13-associated FBXL4 mutations impair the assembly of an active CRL1FBXL4 complex. This results in a notable accumulation of BNIP3/3L proteins and robust mitophagy even at basal levels. Excessive mitophagy was observed in Knockin (KI) mice carrying a patient-derived FBXL4 mutation and cortical neurons (CNs)-induced from MTDPS13 patient human induced pluripotent stem cells (hiPSCs). In summary, our findings suggest that abnormal activation of BNIP3/BNIP3L-dependent mitophagy impairs mitochondrial homeostasis and underlies FBXL4-mutated MTDPS13.

DOI: https://doi.org/10.1038/s41418-023-01205-1
Autophagy Rep. 2023 ;pii: 2242054. [Epub ahead of print]2(1):

Protein disorder in the regulatory control of mitophagy.

Sheridan Mikhail, Scott A Soleimanpour.

  Mitophagy is a central component of the mitochondrial quality control machinery, which is necessary for cellular viability and bioenergetics. The E3 ubiquitin ligase CLEC16A (C-type lectin domain containing 16A) forms a tripartite mitophagy regulatory complex together with the E3 ligase RNF41 (ring finger protein 41) and the ubiquitin-specific peptidase USP8 (ubiquitin specific peptidase 8), yet CLEC16A structural/functional domains relevant for mitophagy are unknown. We identify that CLEC16A contains an internal intrinsically disordered region (IDR), which is important for CLEC16A function and stability. IDRs are flexible domains lacking fixed secondary structure and regulate an emerging number of diverse processes, yet they have been largely unstudied in mitophagy. We observe that the internal CLEC16A IDR is essential for CLEC16A degradation and is bound by RNF41 to promote CLEC16A turnover. This IDR also promotes assembly of the CLEC16A-RNF41-USP8 mitophagy regulatory complex. Thus, our study revealed the importance of IDRs in mitophagy via the regulation of CLEC16A abundance by RNF41, opening new structural insights into mitochondrial quality control.

Keywords:  autophagy; clec16a; intrinsically disordered protein; mitochondria; ubiquitin

DOI:  https://doi.org/10.1080/27694127.2023.2242054
NPJ Parkinsons Dis. 2023 Aug 08. 9(1): 120

Parkinson's disease neurons exhibit alterations in mitochondrial quality control proteins.

Chun Chen, David McDonald, Alasdair Blain, Emily Mossman, Kiera Atkin, Michael F Marusich, Roderick Capaldi, Laura Bone, Anna Smith, Andrew Filby, Daniel Erskine, Oliver Russell, Gavin Hudson, Amy E Vincent, Amy K Reeve.

Mitochondrial dysfunction has been suggested to contribute to Parkinson's disease pathogenesis, though an understanding of the extent or exact mechanism of this contribution remains elusive. This has been complicated by challenging nature of pathway-based analysis and an inability simultaneously study multiple related proteins within human brain tissue. We used imaging mass cytometry (IMC) to overcome these challenges, measuring multiple protein targets, whilst retaining the spatial relationship between targets in post-mortem midbrain sections. We used IMC to simultaneously interrogate subunits of the mitochondrial oxidative phosphorylation complexes, and several key signalling pathways important for mitochondrial homoeostasis, in a large cohort of PD patient and control cases. We revealed a generalised and synergistic reduction in mitochondrial quality control proteins in dopaminergic neurons from Parkinson's patients. Further, protein-protein abundance relationships appeared significantly different between PD and disease control tissue. Our data showed a significant reduction in the abundance of PINK1, Parkin and phosphorylated ubiquitinSer65, integral to the mitophagy machinery; two mitochondrial chaperones, HSP60 and PHB1; and regulators of mitochondrial protein synthesis and the unfolded protein response, SIRT3 and TFAM. Further, SIRT3 and PINK1 did not show an adaptive response to an ATP synthase defect in the Parkinson's neurons. We also observed intraneuronal aggregates of phosphorylated ubiquitinSer65, alongside increased abundance of mitochondrial proteases, LONP1 and HTRA2, within the Parkinson's neurons with Lewy body pathology, compared to those without. Taken together, these findings suggest an inability to turnover mitochondria and maintain mitochondrial proteostasis in Parkinson's neurons. This may exacerbate the impact of oxidative phosphorylation defects and ageing related oxidative stress, leading to neuronal degeneration. Our data also suggest that that Lewy pathology may affect mitochondrial quality control regulation through the disturbance of mitophagy and intramitochondrial proteostasis.

DOI: https://doi.org/10.1038/s41531-023-00564-3
Int J Mol Sci. 2023 Aug 07. pii: 12511. [Epub ahead of print]24(15):

ATAD3A: A Key Regulator of Mitochondria-Associated Diseases.

Liting Chen, Yuchang Li, Alexander Zambidis, Vassilios Papadopoulos.

  Mitochondrial membrane protein ATAD3A is a member of the AAA-domain-containing ATPases superfamily. It is important for the maintenance of mitochondrial DNA, structure, and function. In recent years, an increasing number of ATAD3A mutations have been identified in patients with neurological symptoms. Many of these mutations disrupt mitochondrial structure, function, and dynamics and are lethal to patients at a young age. Here, we summarize the current understanding of the relationship between ATAD3A and mitochondria, including the interaction of ATAD3A with mitochondrial DNA and mitochondrial/ER proteins, the regulation of ATAD3A in cholesterol mitochondrial trafficking, and the effect of known ATAD3A mutations on mitochondrial function. In the current review, we revealed that the oligomerization and interaction of ATAD3A with other mitochondrial/ER proteins are vital for its various functions. Despite affecting different domains of the protein, nearly all documented mutations observed in ATAD3A exhibit either loss-of-function or dominant-negative effects, potentially leading to disruption in the dimerization of ATAD3A; autophagy; mitophagy; alteration in mitochondrial number, size, and cristae morphology; and diminished activity of mitochondrial respiratory chain complexes I, IV, and V. These findings imply that ATAD3A plays a critical role in mitochondrial dynamics, which can be readily perturbed by ATAD3A mutation variants.

Keywords:  ATAD3A; cancer; cholesterol; mitochondria; mitochondrial respiration; mtDNA; mutation; neurological diseases

DOI:  https://doi.org/10.3390/ijms241512511
Free Radic Biol Med. 2023 Aug 09. pii: S0891-5849(23)00581-6. [Epub ahead of print]

The role of mitochondria in myocardial damage caused by energy metabolism disorders: From mechanisms to therapeutics.

Ao-Lin Li, Lu Lian, Xin-Nong Chen, Wen-Hui Cai, Xin-Biao Fan, Ya-Jie Fan, Ting-Ting Li, Ying-Yu Xie, Jun-Ping Zhang.

  Myocardial damage is the most serious pathological consequence of cardiovascular diseases and an important reason for their high mortality. In recent years, because of the high prevalence of systemic energy metabolism disorders (e.g., obesity, diabetes mellitus, and metabolic syndrome), complications of myocardial damage caused by these disorders have attracted widespread attention. Energy metabolism disorders are independent of traditional injury-related risk factors, such as ischemia, hypoxia, trauma, and infection. An imbalance of myocardial metabolic flexibility and myocardial energy depletion are usually the initial changes of myocardial injury caused by energy metabolism disorders, and abnormal morphology and functional destruction of the mitochondria are their important features. Specifically, mitochondria are the centers of energy metabolism, and recent evidence has shown that decreased mitochondrial function, caused by an imbalance in mitochondrial quality control, may play a key role in myocardial injury caused by energy metabolism disorders. Under chronic energy stress, mitochondria undergo pathological fission, while mitophagy, mitochondrial fusion, and biogenesis are inhibited, and mitochondrial protein balance and transfer are disturbed, resulting in the accumulation of nonfunctional and damaged mitochondria. Consequently, damaged mitochondria lead to myocardial energy depletion and the accumulation of large amounts of reactive oxygen species, further aggravating the imbalance in mitochondrial quality control and forming a vicious cycle. In addition, impaired mitochondria coordinate calcium homeostasis imbalance, and epigenetic alterations participate in the pathogenesis of myocardial damage. These pathological changes induce rapid progression of myocardial damage, eventually leading to heart failure or sudden cardiac death. To intervene more specifically in the myocardial damage caused by metabolic disorders, we need to understand the specific role of mitochondria in this context in detail. Accordingly, promising therapeutic strategies have been proposed. We also summarize the existing therapeutic strategies to provide a reference for clinical treatment and developing new therapies.

Keywords:  Calcium homeostasis; Energy metabolism; Epigenetics; Mitochondria; Mitochondrial quality control; Myocardial damage; Oxidative stress; Therapy

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.08.009
Microb Cell. 2023 Aug 07. 10(8): 157-169

Caspase 3 exhibits a yeast metacaspase proteostasis function that protects mitochondria from toxic TDP43 aggregates.

Steve Brunette, Anupam Sharma, Ryan Bell, Lawrence Puente, Lynn A Megeney.

  Caspase 3 activation is a hallmark of cell death and there is a strong correlation between elevated protease activity and evolving pathology in neurodegenerative disease, such as amyotrophic lateral sclerosis (ALS). At the cellular level, ALS is characterized by protein aggregates and inclusions, comprising the RNA binding protein TDP-43, which are hypothesized to trigger pathogenic activation of caspase 3. However, a growing body of evidence indicates this protease is essential for ensuring cell viability during growth, differentiation and adaptation to stress. Here, we explored whether caspase 3 acts to disperse toxic protein aggregates, a proteostasis activity first ascribed to the distantly related yeast metacaspase ScMCA1. We demonstrate that human caspase 3 can functionally substitute for the ScMCA1 and limit protein aggregation in yeast, including TDP-43 inclusions. Proteomic analysis revealed that disrupting caspase 3 in the same yeast substitution model resulted in detrimental TDP-43/mitochondrial protein associations. Similarly, suppression of caspase 3, in either murine or human skeletal muscle cells, led to accumulation of TDP-43 aggregates and impaired mitochondrial function. These results suggest that caspase 3 is not inherently pathogenic, but may act as a compensatory proteostasis factor, to limit TDP-43 protein inclusions and protect organelle function in aggregation related degenerative disease.

Keywords:  TDP43; caspase; metacaspase; protein aggregation; proteostasis; yeast

DOI:  https://doi.org/10.15698/mic2023.08.801
Int J Mol Sci. 2023 Aug 06. pii: 12485. [Epub ahead of print]24(15):

Alterations in Mitochondrial Morphology and Quality Control in Primary Mouse Lung Microvascular Endothelial Cells and Human Dermal Fibroblasts under Hyperglycemic Conditions.

Natalia V Belosludtseva, Dmitriy A Serov, Vlada S Starinets, Nikita V Penkov, Konstantin N Belosludtsev.

  The effect of hyperglycemia on the morphology of individual mitochondria and the state of the mitochondrial network in primary mouse lung microvascular endotheliocytes and human dermal fibroblasts has been investigated. The cells were exposed to high (30 mM) and low (5.5 mM) glucose concentrations for 36 h. In primary endotheliocytes, hyperglycemic stress induced a significant increase in the number of mitochondria and a decrease in the interconnectivity value of the mitochondrial network, which was associated with a decrease in the mean size of the mitochondria. Analysis of the mRNA level of the genes of proteins responsible for mitochondrial biogenesis and mitophagy revealed an increase in the expression level of the Ppargc1a, Pink1, and Parkin genes, indicating stimulated mitochondrial turnover in endotheliocytes under high glucose conditions. In primary fibroblasts, hyperglycemia caused a decrease in the number of mitochondria and an increase in their size. As a result, the mitochondria exhibited higher values for elongation. In parallel, the mRNA level of the Ppargc1a and Mfn2 genes in fibroblasts exposed to hyperglycemia was reduced. These findings indicate that high glucose concentrations induced cell-specific morphological rearrangements of individual mitochondria and the mitochondrial network, which may be relevant during mitochondria-targeted drug testing and therapy for hyperglycemic and diabetic conditions.

Keywords:  diabetic hyperglycemia; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial morphology; mitophagy

DOI:  https://doi.org/10.3390/ijms241512485
Am J Transl Res. 2023 ;15(7): 4912-4921

Knockdown of microRNA-96-5p resists oxidative stress-induced apoptosis in nucleus pulposus cells.

Ji Wang, Ziming Xia, Zhengyi Su, Hong Xue, Chengjun Huang, Ming Su.

BACKGROUND: Intervertebral disc degeneration (IVDD) often leads to low back pain, which severely affects people's quality of life. Oxidative stress (OS) can accelerate nucleus pulposus cell (NPCs) senescence and apoptosis. Exploring the mechanism underlying OS-induced apoptosis is of utmost importance to aid in the development of IVDD treatment.METHODS: In the current study, we tested the function of microRNA-96-5p in H2O2-treated NPCs. Apoptosis and mitophagy-related proteins were examined by western blot. Reactive oxygen species (ROS) generation, mitochondrial membrane potential, and apoptosis of NPCs were evaluated by flow cytometry. A luciferase reporter assay was conducted to confirm the interaction between microRNA-96-5p and Forkhead Box Protein O1 (FOXO1).
RESULTS: H2O2 treatment enhanced apoptosis in NPCs and upregulated the microRNA-96-5p expression. It was shown that knockdown of microRNA-96-5p attenuated H2O2-induced OS and apoptosis. FOXO1 is a direct target of microRNA-96-5p, and knockdown of microRNA-96-5p enhanced PINK1/Parkin-mediated mitophagy by up-regulating FOXO1.
CONCLUSIONS: Collectively, knockdown of microRNA-96-5p enhanced PINK1/Parkin-mediated mitophagy by up-regulating FOXO1. Our results facilitate the understanding of the role of microRNA-96-5p in IVDD and the mechanism of H2O2-induced oxidative damage.

Keywords: FOXO1; MicroRNA-96-5p; intervertebral disc degeneration; mitophagy; nucleus pulposus cells
Cells. 2023 Jul 30. pii: 1969. [Epub ahead of print]12(15):

The Role of Mitophagy in Glaucomatous Neurodegeneration.

Dimitrios Stavropoulos, Manjot K Grewal, Bledi Petriti, Kai-Yin Chau, Christopher J Hammond, David F Garway-Heath, Gerassimos Lascaratos.

  This review aims to provide a better understanding of the emerging role of mitophagy in glaucomatous neurodegeneration, which is the primary cause of irreversible blindness worldwide. Increasing evidence from genetic and other experimental studies suggests that mitophagy-related genes are implicated in the pathogenesis of glaucoma in various populations. The association between polymorphisms in these genes and increased risk of glaucoma is presented. Reduction in intraocular pressure (IOP) is currently the only modifiable risk factor for glaucoma, while clinical trials highlight the inadequacy of IOP-lowering therapeutic approaches to prevent sight loss in many glaucoma patients. Mitochondrial dysfunction is thought to increase the susceptibility of retinal ganglion cells (RGCs) to other risk factors and is implicated in glaucomatous degeneration. Mitophagy holds a vital role in mitochondrial quality control processes, and the current review explores the mitophagy-related pathways which may be linked to glaucoma and their therapeutic potential.

Keywords:  genetics; glaucoma; glaucomatous neurodegeneration; mitochondria; mitochondrial dysfunction; mitophagy; primary open-angle glaucoma

DOI:  https://doi.org/10.3390/cells12151969