bims-mikwok 2023-08-20 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2023–08–20
eight papers selected by
Gavin McStay, Liverpool John Moores University

Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired.
Protective effects of Shen Yuan Dan on myocardial ischemia-reperfusion injury via the regulation of mitochondrial quality control.
When mitophagy dictates the outcome of cellular infection: the case of Brucella abortus.
E4 ubiquitin ligase promotes mitofusin turnover and mitochondrial stress response.
Control of mitochondrial integrity influences oocyte quality during reproductive aging.
Choline dehydrogenase interacts with SQSTM1 to activate mitophagy and promote coelomocyte survival in Apostichopus japonicus following Vibrio splendidus infection.
NLRX1: versatile functions of a mitochondrial NLR protein that controls mitophagy.
The mitophagy pathway and its implications in human diseases.

Nat Commun. 2023 Aug 18. 14(1): 5031

Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired.

Wenjing Liang, Shakti Sagar, Rishith Ravindran, Rita H Najor, Justin M Quiles, Liguo Chi, Rachel Y Diao, Benjamin P Woodall, Leonardo J Leon, Erika Zumaya, Jason Duran, David M Cauvi, Antonio De Maio, Eric D Adler, Åsa B Gustafsson.

Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are normally degraded via intracellular degradation pathways that converge on the lysosome. Here, we identified an alternative mechanism to eliminate mitochondria when lysosomal function is compromised. We show that lysosomal inhibition leads to increased secretion of mitochondria in large extracellular vesicles (EVs). The EVs are produced in multivesicular bodies, and their release is independent of autophagy. Deletion of the small GTPase Rab7 in cells or adult mouse heart leads to increased secretion of EVs containing ubiquitinated cargos, including intact mitochondria. The secreted EVs are captured by macrophages without activating inflammation. Hearts from aged mice or Danon disease patients have increased levels of secreted EVs containing mitochondria indicating activation of vesicular release during cardiac pathophysiology. Overall, these findings establish that mitochondria are eliminated in large EVs through the endosomal pathway when lysosomal degradation is inhibited.

DOI: https://doi.org/10.1038/s41467-023-40680-5
Cardiovasc Diagn Ther. 2023 Apr 28. 13(2): 395-407

Protective effects of Shen Yuan Dan on myocardial ischemia-reperfusion injury via the regulation of mitochondrial quality control.

Zhuhua Zhang, Mingxue Zhou, Hongxu Liu, Wei Liu, Jiaping Chen.

   Background: Myocardial cell death resulting from ischemia-reperfusion (I/R) injury has been a predominant contributor to morbidity and mortality globally. The mitochondria-centered mechanism plays an important role in the formation of I/R injury. This study intended to discuss the protective mechanism of Shen Yuan Dan (SYD) on cardiomyocytes hypoxia-reoxygenation (H/R) injury via the regulation of mitochondrial quality control (MQC). Additionally, this study clarified the mechanism by which SYD suppressed mitophagy activity through the suppression of the PTEN-induced kinase 1 (PINK1)/Parkin pathway.
Methods: To induce cellular injury, H9c2 cardiomyocytes were exposed to H/R stimulation. Following the pretreatment with SYD, cardiomyocytes were subjected to H/R stimulation. Mitochondrial membrane potential (MMP), adenosine triphosphate (ATP), superoxide dismutase (SOD), and methane dicarboxylic aldehyde (MDA) were detected to evaluate the degree of cardiomyocyte mitochondrial damage. Laser confocal microscopy was applied to observe the mitochondrial quality, and the messenger (mRNA) levels of mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), optic atrophy protein 1 (Opa1), dynamin-related protein 1 (Drp1), fission 1 (Fis1), and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in cardiomyocytes were assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Western blotting was employed for the estimation of light chain 3 (LC3)-I, LC3-II, PINK1, and Parkin in cardiomyocytes.
Results: It was discovered that SYD pretreatment elevated MMP in H/R injury cardiomyocytes, enhanced ATP content, activated SOD activity, and reduced MDA level. SYD treatment increased the mRNA levels of Mfn1, Mfn2, Opa1 and PGC-1α decreased the mRNA levels of Drp1 and Fis1, and reduced the protein levels of LC3, PINK1, and Parkin.
Conclusions: SYD plays a protective role in H/R injury to cardiomyocytes by regulating mitochondrial quality. Meanwhile, SYD may inhibit mitophagy activity through inhibiting the PINK1/Parkin pathway. This study provides insights into the underlying mechanism of SYD in alleviating myocardial I/R injury.

Keywords:  Myocardial ischemia-reperfusion injury; PINK1/Parkin pathway; Shen Yuan Dan (SYD); mitochondrial quality control

DOI:  https://doi.org/10.21037/cdt-23-86
Autophagy. 2023 Aug 17. 1-2

When mitophagy dictates the outcome of cellular infection: the case of Brucella abortus.

Jérémy Verbeke, Xavier De Bolle, Thierry Arnould.

  Mitochondria are at the basis of various cellular functions ranging from metabolism and redox homeostasis to inflammation and cell death regulation. Mitochondria therefore constitute an attractive target for invading pathogens to fulfil their infectious cycle. This involves the modulation to their advantage of mitochondrial metabolism and dynamics, including the controlled degradation of mitochondria through mitophagy. Mitophagy might for instance be beneficial for bacterial survival as it can clear bactericidal mitochondrial ROS produced by damaged organelle fragments from the intracellular niche. In the case of the bacterial pathogen Brucella abortus, mitophagy induction has another role in the intracellular lifecycle of the bacteria. Indeed, in our study, we showed that B. abortus triggers an iron-dependent BNIP3L-mediated mitophagy response required for proper bacterial egress and infection of neighboring cells. These results highlight the diversity of mitophagy processes that might be crucial for several stages of cellular infection.

Keywords:  BNIP3L; Brucella; HIF1A; intracellular trafficking; iron; mitophagy

DOI:  https://doi.org/10.1080/15548627.2023.2246354
Mol Cell. 2023 Aug 17. pii: S1097-2765(23)00563-4. [Epub ahead of print]83(16): 2976-2990.e9

E4 ubiquitin ligase promotes mitofusin turnover and mitochondrial stress response.

Vincent Anton, Ira Buntenbroich, Tânia Simões, Mariana Joaquim, Leonie Müller, Reinhard Buettner, Margarete Odenthal, Thorsten Hoppe, Mafalda Escobar-Henriques.

  Ubiquitin-dependent control of mitochondrial dynamics is important for protein quality and neuronal integrity. Mitofusins, mitochondrial fusion factors, can integrate cellular stress through their ubiquitylation, which is carried out by multiple E3 enzymes in response to many different stimuli. However, the molecular mechanisms that enable coordinated responses are largely unknown. Here we show that yeast Ufd2, a conserved ubiquitin chain-elongating E4 enzyme, is required for mitochondrial shape adjustments. Under various stresses, Ufd2 translocates to mitochondria and triggers mitofusin ubiquitylation. This elongates ubiquitin chains on mitofusin and promotes its proteasomal degradation, leading to mitochondrial fragmentation. Ufd2 and its human homologue UBE4B also target mitofusin mutants associated with Charcot-Marie-Tooth disease, a hereditary sensory and motor neuropathy characterized by progressive loss of the peripheral nerves. This underscores the pathophysiological importance of E4-mediated ubiquitylation in neurodegeneration. In summary, we identify E4-dependent mitochondrial stress adaptation by linking various metabolic processes to mitochondrial fusion and fission dynamics.

Keywords:  CMT2A; Cdc48/p97; E4; Fzo1; MFN2; UBE4B; Ufd2; fusion; mitochondria; mitofusin; stress; ubiquitin

DOI:  https://doi.org/10.1016/j.molcel.2023.07.021
Mol Hum Reprod. 2023 Aug 18. pii: gaad028. [Epub ahead of print]

Control of mitochondrial integrity influences oocyte quality during reproductive aging.

Shaihla A Khan, Laura Reed, William B Schoolcraft, Ye Yuan, Rebecca L Krisher.

  Reduced quality in oocytes from women of advanced maternal age is associated with dysfunctional mitochondria. The objective of this study was to investigate the mechanisms controlling mitochondrial quality during maternal aging in mouse and human oocytes. We first evaluated the expression of proteins involved in the mitochondrial unfolded protein response (UPRmt) and mitophagy in in-vivo matured metaphase II oocytes collected from young and aged mice. Expression of UPRmt proteins, HSPD1 and LONP1, and mitophagy proteins, total-PRKN and phosphorylated-PRKN, was significantly decreased in aged compared to young oocytes. Treatment of aged oocytes during in-vitro maturation with the mitochondrially targeted antioxidant mitoquinone (MQ) specifically restored total-PRKN and phosphorylated-PRKN expression to levels seen in young oocytes. We next investigated whether maturing young oocytes under a high oxygen environment would mimic the effects observed in oocytes from aged females. Phosphorylated-PRKN expression in oxidatively stressed young oocytes was reduced compared to that in oocytes matured under normal oxygen levels and the mitochondrial DNA (mtDNA) copy number was increased. Treating oxidatively challenged young oocytes with MQ restored the phosphorylated-PRKN expression and mtDNA copy numbers. Treatment of oxidatively challenged oocytes with MQ also increased the co-localization of mitochondria and lysosomes, suggesting increased mitophagy. These data correlated with the developmental potential of the oocytes, as blastocyst development and hatching of oxidatively stressed oocytes was reduced, while treatment with MQ resulted in a significant increase in blastocyst development and hatching, and in the percentage of inner cell mass. Consistent with our results in mice, metaphase II oocytes from women of advanced maternal age exhibited a significant decrease in phosphorylated-PKRN and total-PRKN compared to those of young women. Our findings suggest that the protein machinery to control the health of the mitochondria via UPRmt and mitophagy may be compromised in oocytes from aged females, which may result in inefficient clearance of dysfunctional mitochondria and reduced oocyte quality.

Keywords:  advanced maternal age; mitochondria; mitochondrial unfolded protein response; mitophagy; oocyte

DOI:  https://doi.org/10.1093/molehr/gaad028
Zool Res. 2023 Sep 18. pii: 2095-8137(2023)05-0905-14. [Epub ahead of print]44(5): 905-918

Choline dehydrogenase interacts with SQSTM1 to activate mitophagy and promote coelomocyte survival in Apostichopus japonicus following Vibrio splendidus infection.

Lian-Lian Sun, Ying-Fen Dai, Mei-Xiang You, Cheng-Hua Li.

  Previous studies have shown that Vibrio splendidus infection causes mitochondrial damage in Apostichopus japonicus coelomocytes, leading to the production of excessive reactive oxygen species (ROS) and irreversible apoptotic cell death. Emerging evidence suggests that mitochondrial autophagy (mitophagy) is the most effective method for eliminating damaged mitochondria and ROS, with choline dehydrogenase (CHDH) identified as a novel mitophagy receptor that can recognize non-ubiquitin damage signals and microtubule-associated protein 1 light chain 3 (LC3) in vertebrates. However, the functional role of CHDH in invertebrates is largely unknown. In this study, we observed a significant increase in the mRNA and protein expression levels of A. japonicus CHDH (AjCHDH) in response to V. splendidus infection and lipopolysaccharide (LPS) challenge, consistent with changes in mitophagy under the same conditions. Notably, AjCHDH was localized to the mitochondria rather than the cytosol following V. splendidus infection. Moreover, AjCHDH knockdown using siRNA transfection significantly reduced mitophagy levels, as observed through transmission electron microscopy and confocal microscopy. Further investigation into the molecular mechanisms underlying CHDH-regulated mitophagy showed that AjCHDH lacked an LC3-interacting region (LIR) for direct binding to LC3 but possessed a FB1 structural domain that binds to SQSTM1. The interaction between AjCHDH and SQSTM1 was further confirmed by immunoprecipitation analysis. Furthermore, laser confocal microscopy indicated that SQSTM1 and LC3 were recruited by AjCHDH in coelomocytes and HEK293T cells. In contrast, AjCHDH interference hindered SQSTM1 and LC3 recruitment to the mitochondria, a critical step in damaged mitochondrial degradation. Thus, AjCHDH interference led to a significant increase in both mitochondrial and intracellular ROS, followed by increased apoptosis and decreased coelomocyte survival. Collectively, these findings indicate that AjCHDH-mediated mitophagy plays a crucial role in coelomocyte survival in A. japonicus following V. splendidus infection.

Keywords:  Apostichopus japonicus; Choline dehydrogenase; Microtubule-associated protein 1 light chain 3; Mitophagy; SQSTM1

DOI:  https://doi.org/10.24272/j.issn.2095-8137.2023.106
Biomed J. 2023 Aug 11. pii: S2319-4170(23)00072-0. [Epub ahead of print] 100635

NLRX1: versatile functions of a mitochondrial NLR protein that controls mitophagy.

Paul Y Bi, Samuel A Killackey, Linus Schweizer, Stephen E Girardin.

NLRX1 is a member of the of the Nod-like receptor (NLR) family, and it represents a unique pattern recognition molecule (PRM) as it localizes to the mitochondrial matrix in resting conditions. Over the past fifteen years, NLRX1 has been proposed to regulate multiple cellular processes, including antiviral immunity, apoptosis, reactive oxygen species (ROS) generation and mitochondrial metabolism. Similarly, in vivo models have shown that NLRX1 was associated with the control of a number of diseases, including multiple sclerosis, colorectal cancer and ischemia-reperfusion injury. This apparent versatility in function hinted that a common and general overarching role for NLRX1 may exist. Recent evidence has suggested that NLRX1 controls mitophagy through the detection of a specific "danger signal", namely the defective import of proteins into mitochondria, or mitochondrial protein import stress (MPIS). In this review article, we propose that mitophagy regulation may represent the overarching process detected by NLRX1, which could in turn impact on a number of diseases if dysfunctional.

DOI: https://doi.org/10.1016/j.bj.2023.100635
Signal Transduct Target Ther. 2023 08 16. 8(1): 304

The mitophagy pathway and its implications in human diseases.

Shouliang Wang, Haijiao Long, Lianjie Hou, Baorong Feng, Zihong Ma, Ying Wu, Yu Zeng, Jiahao Cai, Da-Wei Zhang, Guojun Zhao.

Mitochondria are dynamic organelles with multiple functions. They participate in necrotic cell death and programmed apoptotic, and are crucial for cell metabolism and survival. Mitophagy serves as a cytoprotective mechanism to remove superfluous or dysfunctional mitochondria and maintain mitochondrial fine-tuning numbers to balance intracellular homeostasis. Growing evidences show that mitophagy, as an acute tissue stress response, plays an important role in maintaining the health of the mitochondrial network. Since the timely removal of abnormal mitochondria is essential for cell survival, cells have evolved a variety of mitophagy pathways to ensure that mitophagy can be activated in time under various environments. A better understanding of the mechanism of mitophagy in various diseases is crucial for the treatment of diseases and therapeutic target design. In this review, we summarize the molecular mechanisms of mitophagy-mediated mitochondrial elimination, how mitophagy maintains mitochondrial homeostasis at the system levels and organ, and what alterations in mitophagy are related to the development of diseases, including neurological, cardiovascular, pulmonary, hepatic, renal disease, etc., in recent advances. Finally, we summarize the potential clinical applications and outline the conditions for mitophagy regulators to enter clinical trials. Research advances in signaling transduction of mitophagy will have an important role in developing new therapeutic strategies for precision medicine.

DOI: https://doi.org/10.1038/s41392-023-01503-7