bims-mitpro 2023-10-22 papers

bims-mitpro

Biomed News

on Mitochondrial proteostasis

Issue of 2023–10–22
ten papers selected by
Andreas Kohler, Umeå University

A PINK1 input threshold arises from positive feedback in the PINK1/Parkin mitophagy decision circuit.
ATAD3 Proteins: Unique Mitochondrial Proteins Essential for Life in Diverse Eukaryotic Lineages.
GLIS1 alleviates cell senescence and renal fibrosis through PGC1-α mediated mitochondrial quality control in kidney aging.
Mitophagy in neurodegenerative disease pathogenesis.
Mitochondria-lysosome-related organelles mediate mitochondrial clearance during cellular dedifferentiation.
Targeting mitochondrial degradation by chimeric autophagy-tethering compounds.
5-Heptadecylresorcinol Ameliorates Obesity-Associated Skeletal Muscle Mitochondrial Dysfunction through SIRT3-Mediated Mitophagy.
ATF5-regulated Mitochondrial Unfolded Protein Response Attenuates Neuronal Damage in Epileptic Rat by Reducing Endoplasmic Reticulum Stress Through Mitochondrial ROS.
Mitochondrial dysfunction and quality control lie at the heart of subarachnoid hemorrhage.
Mitophagy in yeast: known unknowns and unknown unknowns.

Cell Rep. 2023 Oct 17. pii: S2211-1247(23)01272-X. [Epub ahead of print]42(10): 113260

A PINK1 input threshold arises from positive feedback in the PINK1/Parkin mitophagy decision circuit.

Christopher S Waters, Sigurd B Angenent, Steven J Altschuler, Lani F Wu.

  Mechanisms that prevent accidental activation of the PINK1/Parkin mitophagy circuit on healthy mitochondria are poorly understood. On the surface of damaged mitochondria, PINK1 accumulates and acts as the input signal to a positive feedback loop of Parkin recruitment, which in turn promotes mitochondrial degradation via mitophagy. However, PINK1 is also present on healthy mitochondria, where it could errantly recruit Parkin and thereby activate this positive feedback loop. Here, we explore emergent properties of the PINK1/Parkin circuit by quantifying the relationship between mitochondrial PINK1 concentrations and Parkin recruitment dynamics. We find that Parkin is recruited to mitochondria only if PINK1 levels exceed a threshold and then only after a delay that is inversely proportional to PINK1 levels. Furthermore, these two regulatory properties arise from the input-coupled positive feedback topology of the PINK1/Parkin circuit. These results outline an intrinsic mechanism by which the PINK1/Parkin circuit can avoid errant activation on healthy mitochondria.

Keywords:  CP: Molecular biology; PINK1; Parkin; circuit; delay; mathematical model; mitophagy decision; quantitative microscopy; synthetic biology; systems biology; threshold

DOI:  https://doi.org/10.1016/j.celrep.2023.113260
Plant Cell Physiol. 2023 Oct 19. pii: pcad122. [Epub ahead of print]

ATAD3 Proteins: Unique Mitochondrial Proteins Essential for Life in Diverse Eukaryotic Lineages.

Elizabeth R Waters, Magdalena Bezanilla, Elizabeth Vierling.

  ATAD3 proteins (ATPase family AAA domain-containing protein 3) are unique mitochondrial proteins that arose deep in the eukaryotic lineage but that are surprisingly absent from the Fungi and Amoebozoa. These ~600 amino acid proteins are anchored in the inner mitochondrial membrane and are essential in metazoans and Arabidopsis thaliana. ATAD3s comprise a C-terminal AAA+ matrix domain and an ATAD3_N domain that is located primarily in the inner membrane space but potentially extends into cytosol to interact with the ER. Sequence and structural alignments indicate ATAD3 proteins are most similar to classic chaperone unfoldases in AAA+ family, suggesting that they operate in mitochondrial protein quality control. A. thaliana has four ATAD3 genes in two distinct clades that appear first in the seed plants, and both clades are essential for viability. The four genes are generally coordinately expressed, and transcripts are highest in growing apices and imbibed seeds. Plants with disrupted ATAD3 have reduced growth, aberrant mitochondrial morphology, diffuse nucleoids and reduced oxidative phosphorylation complex I. These and other pleiotropic phenotypes are also observed in ATAD3 mutants in metazoans. Here we discuss the distribution of ATAD3 proteins as they have evolved in the plant kingdom, their unique structure, what we know about their function in plants, and the challenges in determining their essential roles in mitochondria.

Keywords:   Arabidopsis thaliana ; eukaryotic evolution; membrane contact sites; nucleoids; oxidative phosphorylation; protein quality control

DOI:  https://doi.org/10.1093/pcp/pcad122
Free Radic Biol Med. 2023 Oct 16. pii: S0891-5849(23)00662-7. [Epub ahead of print]

GLIS1 alleviates cell senescence and renal fibrosis through PGC1-α mediated mitochondrial quality control in kidney aging.

Li Xu, Jiao Wang, Hongyuan Yu, Hang Mei, Ping He, Min Wang, Yue Liu, Qiuling Fan, Ying Chen, Yanqiu Li, Fan Liu.

  Mitochondrial dysfunction is implied as a crucial factor in age-related chronic kidney disease. It is confirmed that Gli-like transcription factor 1 (GLIS1) is involved in age-related renal fibrosis, however, the correlation between mitochondrial disturbances and GLIS1-driven kidney aging are not clearly clarified. Thus, we investigated the regulatory mechanism of GLIS1 in the homeostasis of mitochondrial quality control both in vivo and in vitro. The lower expression of GLIS1 was identified in natural and accelerated kidney aged models, accompanied by the dysfunctions of mitochondrial quality control, including enhanced mitochondrial fission, reduced mitochondrial biogenesis and mitophagy, whereas, GLIS1 could maintain mitochondrial stability by interacting with peroxisome proliferator-activated receptor γ coactivator-1α (PGC1-α). Additionally, the over-expressed GLIS1 inhibited extracellular matrix accumulation and alleviated renal fibrosis while siGLIS1 inhibited PGC1-α transcription, as well as affecting its mitochondria-protective functions. Collectively, we demonstrated that GLIS1 mediated mitochondrial quality control through targeting PGC1-α in kidney aging, which might be a promising therapeutic target for attenuating cell senescence and age-related renal fibrosis.

Keywords:  GLIS1; Kidney aging; Mitochondrial quality control; PGC1-α; Renal fibrosis

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.09.037
Neural Regen Res. 2024 May;19(5): 998-1005

Mitophagy in neurodegenerative disease pathogenesis.

Kan Yang, Yuqing Yan, Anni Yu, Ru Zhang, Yuefang Zhang, Zilong Qiu, Zhengyi Li, Qianlong Zhang, Shihao Wu, Fei Li.

  Mitochondria are critical cellular energy resources and are central to the life of the neuron. Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and homeostasis. Mature neurons are postmitotic and consume substantial energy, thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional mitochondria. Recent evidence indicates that mitophagy is pivotal to the pathogenesis of neurological diseases. However, more work is needed to study mitophagy pathway components as potential therapeutic targets. In this review, we briefly discuss the characteristics of nonselective autophagy and selective autophagy, including ERphagy, aggrephagy, and mitophagy. We then introduce the mechanisms of Parkin-dependent and Parkin-independent mitophagy pathways under physiological conditions. Next, we summarize the diverse repertoire of mitochondrial membrane receptors and phospholipids that mediate mitophagy. Importantly, we review the critical role of mitophagy in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Last, we discuss recent studies considering mitophagy as a potential therapeutic target for treating neurodegenerative diseases. Together, our review may provide novel views to better understand the roles of mitophagy in neurodegenerative disease pathogenesis.

Keywords:  Alzheimer’s disease; PINK1; Parkin; Parkinson’s disease; amyotrophic lateral sclerosis; autophagy; mitochondria; mitophagy; mitophagy receptor

DOI:  https://doi.org/10.4103/1673-5374.385281
Cell Rep. 2023 Oct 19. pii: S2211-1247(23)01303-7. [Epub ahead of print]42(10): 113291

Mitochondria-lysosome-related organelles mediate mitochondrial clearance during cellular dedifferentiation.

Xiaowen Ma, Sharon Manley, Hui Qian, Yuan Li, Chen Zhang, Kevin Li, Benjamin Ding, Fengli Guo, Allen Chen, Xing Zhang, Meilian Liu, Meihua Hao, Benjamin Kugler, E Matthew Morris, John Thyfault, Ling Yang, Hiromi Sesaki, Hong-Min Ni, Heidi McBride, Wen-Xing Ding.

  Dysfunctional mitochondria are removed via multiple pathways, such as mitophagy, a selective autophagy process. Here, we identify an intracellular hybrid mitochondria-lysosome organelle (termed the mitochondria-lysosome-related organelle [MLRO]), which regulates mitochondrial homeostasis independent of canonical mitophagy during hepatocyte dedifferentiation. The MLRO is an electron-dense organelle that has either a single or double membrane with both mitochondria and lysosome markers. Mechanistically, the MLRO is likely formed from the fusion of mitochondria-derived vesicles (MDVs) with lysosomes through a PARKIN-, ATG5-, and DRP1-independent process, which is negatively regulated by transcription factor EB (TFEB) and associated with mitochondrial protein degradation and hepatocyte dedifferentiation. The MLRO, which is galectin-3 positive, is reminiscent of damaged lysosome and could be cleared by overexpression of TFEB, resulting in attenuation of hepatocyte dedifferentiation. Together, results from this study suggest that the MLRO may act as an alternative mechanism for mitochondrial quality control independent of canonical autophagy/mitophagy involved in cell dedifferentiation.

Keywords:  ATG5; CP: Cell biology; DRP1; autophagy; hepatocytes; lysosome; mitophagy

DOI:  https://doi.org/10.1016/j.celrep.2023.113291
Chem Sci. 2023 Oct 18. 14(40): 11192-11202

Targeting mitochondrial degradation by chimeric autophagy-tethering compounds.

Zhenqi Liu, Geng Qin, Jie Yang, Wenjie Wang, Wenting Zhang, Boxun Lu, Jinsong Ren, Xiaogang Qu.

The ability to regulate mitophagy in a living system with small molecules remains a great challenge. We hypothesize that adding fragments specific to the key autophagosome protein LC3 to mitochondria will mimic receptor-mediated mitophagy, thus engaging the autophagy-lysosome pathway to induce mitochondrial degradation. Herein, we develop a general biochemical approach to modulate mitophagy, dubbed mito-ATTECs, which employ chimera molecules composed of LC3-binding moieties linked to mitochondria-targeting ligands. Mito-ATTECs trigger mitophagy via targeting mitochondria to autophagosomes through direct interaction between mito-ATTECs and LC3 on mitochondrial membranes. Subsequently, autophagosomes containing mitochondria rapidly fuse with lysosomes to facilitate the degradation of mitochondria. Therefore, mito-ATTECs circumvent the detrimental effects related to disruption of mitochondrial membrane integrity by inducers routinely used to manipulate mitophagy, and provide a versatile biochemical approach to investigate the physiological roles of mitophagy. Furthermore, we found that sustained mitophagy lead to mitochondrial depletion and autophagic cell death in several malignant cell lines (lethal mitophagy). Among them, apoptosis-resistant malignant melanoma cell lines are particularly sensitive to lethal mitophagy. The therapeutic efficacy of mito-ATTECs has been further evaluated by using subcutaneous and pulmonary metastatic melanoma models. Together, the mitochondrial depletion achieved by mito-ATTECs may demonstrate the general concept of inducing cancer cell lethality through excessive mitochondrial clearance, establishing a promising therapeutic paradigm for apoptosis-resistant tumors.

DOI: https://doi.org/10.1039/d3sc03600f
J Agric Food Chem. 2023 Oct 20.

5-Heptadecylresorcinol Ameliorates Obesity-Associated Skeletal Muscle Mitochondrial Dysfunction through SIRT3-Mediated Mitophagy.

Ziyuan Wang, Qing Li, Haihong Yang, Dandan Zhang, Yiman Zhang, Jing Wang, Jie Liu.

  Skeletal muscle dysfunction caused by obesity is characterized by the decline in mitochondrial content and function. 5-Heptadecylresorcinol (AR-C17) is a specific bioactive component derived from whole wheat and rye, which has been evidenced to improve obesity-associated skeletal muscle dysregulation. However, the mechanism underlying its protective activity requires further exploration. Herein, we found that AR-C17 (5, 10, and 20 μM) intervention reversed PA-induced (0.5 mM) reduction in mitochondrial content, mitochondrial membrane potential, and mitochondrial energy metabolism in C2C12 cells. Meanwhile, AR-C17 evidently alleviated PA-mediated myotube mitochondrial dysfunction via elevating mitochondria autophagy flux and upregulating the expression level of autophagy-related protein, while this effect was abolished by an autophagy inhibitor (3-MA). Further analysis showed that SIRT3-FOXO3A-PINK-Parkin-mediated mitophagy was involved in the modulation of myocyte mitochondrial dysfunction by AR-C17. In addition, AR-C17 administration (30 and 150 mg/kg/day) significantly improved high-fat-diet-induced mitochondrial dysregulation in mice skeletal muscle tissue via SIRT3-dependent mitophagy. Our findings indicate that skeletal muscle cells are responsive to AR-C17, which improves myogenesis and mitophagy in vitro and in vivo.

Keywords:  5-heptadecylresorcinol; SIRT3; mitochondrial function; mitophagy; skeletal muscle

DOI:  https://doi.org/10.1021/acs.jafc.3c01452
Neurochem Res. 2023 Oct 17.

ATF5-regulated Mitochondrial Unfolded Protein Response Attenuates Neuronal Damage in Epileptic Rat by Reducing Endoplasmic Reticulum Stress Through Mitochondrial ROS.

Xiaolei Lian, Xiaoyi Wang, Yinyin Xie, Hanqing Sheng, Jiao He, Tingting Peng, Nanchang Xie, Cui Wang, Yajun Lian.

  Endoplasmic reticulum (ER) dysfunction caused by excessive ER stress is a crucial mechanism underlying seizures-induced neuronal injury. Studies have shown that mitochondrial reactive oxygen species (ROS) are closely related to ER stress, and our previous study showed that activating transcription factor 5 (ATF5)-regulated mitochondrial unfolded protein response (mtUPR) modulated mitochondrial ROS generation in a hippocampal neuronal culture model of seizures. However, the effects of ATF5-regulated mtUPR on ER stress and the underlying mechanisms remain uncertain in epilepsy. In this study, ATF5 upregulation by lentivirus infection attenuated seizures-induced neuronal damage and apoptosis in a rat model of pilocarpine-induced epilepsy, whereas ATF5 downregulation by lentivirus infection had the opposite effects. ATF5 upregulation potentiated mtUPR by increasing the expression of mitochondrial chaperone heat shock protein 60 (HSP60) and caseinolytic protease proteolytic subunit (ClpP) and reducing mitochondrial ROS generation in pilocarpine-induced seizures in rats. Additionally, upregulation of ATF5 reduced the expression of glucose-regulated protein 78 (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP), suggesting suppression of ER stress; Moreover, ATF5 upregulation attenuated apoptosis-related proteins such as B-cell lymphoma-2 (BCL2) downregulation, BCL2-associated X (BAX) and cleaved-caspase-3 upregulation. However, ATF5 downregulation exerted the opposite effects. Furthermore, pretreatment with the mitochondria-targeted antioxidant mito-TEMPO attenuated the harmful effects of ATF5 downregulation on ER stress and neuronal apoptosis by reducing mitochondrial ROS generation. Overall, our study suggested that ATF5-regulated mtUPR exerted neuroprotective effects against pilocarpine-induced seizures in rats and the underlying mechanisms might involve mitochondrial ROS-mediated ER stress.

Keywords:  Activating transcription factor 5; Endoplasmic reticulum stress; Mitochondrial reactive oxygen species; Mitochondrial unfolded protein response; Seizures

DOI:  https://doi.org/10.1007/s11064-023-04042-3
Neural Regen Res. 2024 Apr;19(4): 825-832

Mitochondrial dysfunction and quality control lie at the heart of subarachnoid hemorrhage.

Jiatong Zhang, Qi Zhu, Jie Wang, Zheng Peng, Zong Zhuang, Chunhua Hang, Wei Li.

  The dramatic increase in intracranial pressure after subarachnoid hemorrhage leads to a decrease in cerebral perfusion pressure and a reduction in cerebral blood flow. Mitochondria are directly affected by direct factors such as ischemia, hypoxia, excitotoxicity, and toxicity of free hemoglobin and its degradation products, which trigger mitochondrial dysfunction. Dysfunctional mitochondria release large amounts of reactive oxygen species, inflammatory mediators, and apoptotic proteins that activate apoptotic pathways, further damaging cells. In response to this array of damage, cells have adopted multiple mitochondrial quality control mechanisms through evolution, including mitochondrial protein quality control, mitochondrial dynamics, mitophagy, mitochondrial biogenesis, and intercellular mitochondrial transfer, to maintain mitochondrial homeostasis under pathological conditions. Specific interventions targeting mitochondrial quality control mechanisms have emerged as promising therapeutic strategies for subarachnoid hemorrhage. This review provides an overview of recent research advances in mitochondrial pathophysiological processes after subarachnoid hemorrhage, particularly mitochondrial quality control mechanisms. It also presents potential therapeutic strategies to target mitochondrial quality control in subarachnoid hemorrhage.

Keywords:  mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial fission and fusion; mitochondrial quality control; mitophagy; subarachnoid hemorrhage

DOI:  https://doi.org/10.4103/1673-5374.381493
Biochem J. 2023 Oct 31. 480(20): 1639-1657

Mitophagy in yeast: known unknowns and unknown unknowns.

Hagai Abeliovich.

  Mitophagy, the autophagic breakdown of mitochondria, is observed in eukaryotic cells under various different physiological circumstances. These can be broadly categorized into two types: mitophagy related to quality control events and mitophagy induced during developmental transitions. Quality control mitophagy involves the lysosomal or vacuolar degradation of malfunctioning or superfluous mitochondria within lysosomes or vacuoles, and this is thought to serve as a vital maintenance function in respiring eukaryotic cells. It plays a crucial role in maintaining physiological balance, and its disruption has been associated with the progression of late-onset diseases. Developmentally induced mitophagy has been reported in the differentiation of metazoan tissues which undergo metabolic shifts upon developmental transitions, such as in the differentiation of red blood cells and muscle cells. Although the mechanistic studies of mitophagy in mammalian cells were initiated after the initial mechanistic findings in Saccharomyces cerevisiae, our current understanding of the physiological role of mitophagy in yeast remains more limited, despite the presence of better-defined assays and tools. In this review, I present my perspective on our present knowledge of mitophagy in yeast, focusing on physiological and mechanistic aspects. I aim to focus on areas where our understanding is still incomplete, such as the role of mitochondrial dynamics and the phenomenon of protein-level selectivity.

Keywords:   Saccharomyces cerevisiae ; autophagy; mitophagy

DOI:  https://doi.org/10.1042/BCJ20230279