bims-tofagi 2023-11-12 papers

on Mitophagy

Issue of 2023–11–12
thirteen papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea

Aggregation of alpha-synuclein disrupts mitochondrial metabolism and induce mitophagy via cardiolipin externalization.
Mitophagy Activation by Urolithin A to Target Muscle Aging.
FUNDC1 collaborates with PINK1 in regulating mitochondrial Fission and compensating for PINK1 deficiency.
Mitochondrial Inherited Disorders and their Correlation with Neurodegenerative Diseases.
Targeted clearance of mitochondria by an autophagy-tethering compound (ATTEC) and its potential therapeutic effects.
NDP52 SUMOylation contributes to low-dose X-rays-induced cardiac hypertrophy through PINK1/Parkin-mediated mitophagy via MUL1/SUMO2 signalling.
Post-Subfunctionalization Functions of HIF-1αA and HIF-1αB in Cyprinid Fish: Fine-Tuning Mitophagy and Apoptosis Regulation Under Hypoxic Stress.
PTEN-induced kinase 1 exerts protective effects in diabetic kidney disease by attenuating mitochondrial dysfunction and necroptosis.
Mitophagy-dependent Cardioprotection of Resistance Training on Heart Failure.
Reducing myocardial infarction by combination of irisin and Dendrobium nobile Lindl through inhibiting nod-like receptor protein-3-related pyroptosis and activating PINK1/Parkin-mitophagy during aging.
Effects of dapagliflozin monotherapy and combined aerobic exercise on skeletal muscle mitochondrial quality control and insulin resistance in type 2 diabetes mellitus rats.
Erxian Decoction-induced serum exosomes slowed bone marrow mesenchymal stem cell senescence through mitophagy.
PINK1-PTEN axis promotes metastasis and chemoresistance in ovarian cancer via non-canonical pathway.

Cell Death Dis. 2023 Nov 10. 14(11): 729

Aggregation of alpha-synuclein disrupts mitochondrial metabolism and induce mitophagy via cardiolipin externalization.

Olivier Lurette, Rebeca Martín-Jiménez, Mehtab Khan, Razan Sheta, Stéphanie Jean, Mia Schofield, Maxime Teixeira, Raquel Rodriguez-Aller, Isabelle Perron, Abid Oueslati, Etienne Hebert-Chatelain.

Accumulation of α-synuclein aggregates in the substantia nigra pars compacta is central in the pathophysiology of Parkinson's disease, leading to the degeneration of dopaminergic neurons and the manifestation of motor symptoms. Although several PD models mimic the pathological accumulation of α-synuclein after overexpression, they do not allow for controlling and monitoring its aggregation. We recently generated a new optogenetic tool by which we can spatiotemporally control the aggregation of α-synuclein using a light-induced protein aggregation system. Using this innovative tool, we aimed to characterize the impact of α-synuclein clustering on mitochondria, whose activity is crucial to maintain neuronal survival. We observed that aggregates of α-synuclein transiently and dynamically interact with mitochondria, leading to mitochondrial depolarization, lower ATP production, mitochondrial fragmentation and degradation via cardiolipin externalization-dependent mitophagy. Aggregation of α-synuclein also leads to lower mitochondrial content in human dopaminergic neurons and in mouse midbrain. Interestingly, overexpression of α-synuclein alone did not induce mitochondrial degradation. This work is among the first to clearly discriminate between the impact of α-synuclein overexpression and aggregation on mitochondria. This study thus represents a new framework to characterize the role of mitochondria in PD.

DOI: https://doi.org/10.1038/s41419-023-06251-8
Calcif Tissue Int. 2023 Nov 05.

Mitophagy Activation by Urolithin A to Target Muscle Aging.

Julie Faitg, Davide D'Amico, Chris Rinsch, Anurag Singh.

  The age-related loss of skeletal muscle function starts from midlife and if left unaddressed can lead to an impaired quality of life. A growing body of evidence indicates that mitochondrial dysfunction is causally involved with muscle aging. Muscles are tissues with high metabolic requirements, and contain rich mitochondria supply to support their continual energy needs. Cellular mitochondrial health is maintained by expansing of the mitochondrial pool though mitochondrial biogenesis, by preserving the natural mitochondrial dynamic process, via fusion and fission, and by ensuring the removal of damaged mitochondria through mitophagy. During aging, mitophagy levels decline and negatively impact skeletal muscle performance. Nutritional and pharmacological approaches have been proposed to manage the decline in muscle function due to impaired mitochondria bioenergetics. The natural postbiotic Urolithin A has been shown to promote mitophagy, mitochondrial function and improved muscle function across species in different experimental models and across multiple clinical studies. In this review, we explore the biology of Urolithin A and the clinical evidence of its impact on promoting healthy skeletal muscles during age-associated muscle decline.

Keywords:  Aging; Mitochondria; Mitophagy; Muscle health; Urolithin A

DOI:  https://doi.org/10.1007/s00223-023-01145-5
Biochem Biophys Res Commun. 2023 Nov 01. pii: S0006-291X(23)01304-9. [Epub ahead of print]687 149210

FUNDC1 collaborates with PINK1 in regulating mitochondrial Fission and compensating for PINK1 deficiency.

Jing Xu, Zhouyang Deng, Shuai Shang, Caifang Wang, Hailong Han.

  Parkinson's disease is presently thought to have its molecular roots in the alteration of PINK1-mediated mitophagy and mitochondrial dynamics. Finding new suppressors of the pathway is essential for developing cutting-edge treatment approaches. Our study shows that FUNDC1 suppressed PINK1 mutant phenotypes in Drosophila. The restoration of PINK1-deficient phenotypes through FUNDC1 is not reliant on its LC3-binding motif Y (18)L (21) or autophagy-related pathway. Moreover, the absence of Drp1 affects the phenotypic restoration of PINK1 mediated by FUNDC1 in flies. In summary, our findings have unveiled a fresh mechanism through which FUNDC1 compensates for the loss of PINK1, operating independently of autophagy but exerting its influence via interaction with Drp1.

Keywords:  Autophagy receptor; Drp1; Mitochondrial dynamics; PD; Ubiquitin-independent mitophagy

DOI:  https://doi.org/10.1016/j.bbrc.2023.149210
Endocr Metab Immune Disord Drug Targets. 2023 Nov 01.

Mitochondrial Inherited Disorders and their Correlation with Neurodegenerative Diseases.

Sofjana Gushi, Dr Vasileios Balis PhD Mrsb.

  Mitochondria are essential organelles for the survival of a cell because they produce energy. The cells that need more mitochondria are neurons because they perform a variety of tasks that are necessary to support brain homeostasis. The build-up of abnormal proteins in neurons, as well as their interactions with mitochondrial proteins, or MAM proteins, cause serious health issues. As a result, mitochondrial functions, such as mitophagy, are impaired, resulting in the disorders described in this review. They are also due to mtDNA mutations, which alter the heritability of diseases. The topic of disease prevention, as well as the diagnosis, requires further explanation and exploration. Finally, there are treatments that are quite promising, but more detailed research is needed.

Keywords:  Mitochondria; diagnosis; heritability.; mitochondrial DNA; mitophagy; neurodegeneration; prevention; treatment

DOI:  https://doi.org/10.2174/0118715303250271231018103202
Sci Bull (Beijing). 2023 Oct 26. pii: S2095-9273(23)00721-1. [Epub ahead of print]

Targeted clearance of mitochondria by an autophagy-tethering compound (ATTEC) and its potential therapeutic effects.

Shuixia Tan, Da Wang, Yuhua Fu, Huiwen Zheng, Yan Liu, Boxun Lu.

  Increased mitochondrial damage plays a critical role in many neurodegeneration-related diseases such as Parkinson's disease (PD) and Down syndrome (DS). Thus, enhancement of mitochondrial degradation by small molecule compounds may provide promising new strategies to tackle these diseases. Here, we explored the strategy to induce clearance of mitochondria by targeting them to the autophagy machinery by autophagy-tethering compounds (ATTECs). We provided the proof-of-concept evidence demonstrating that the bifunctional compound (mT1) binding to both the outer mitochondrial membrane protein TSPO and the autophagosome protein LC3B simultaneously may enhance the engulfment of damaged mitochondria by autophagosomes and subsequent autophagic degradation of them. In addition, preliminary experiments suggest that mT1 attenuated disease-relevant phenotypes in both a PD cellular model and a DS organoid model. Taken together, we demonstrate the possibility of degrading mitochondria by bifunctional ATTECs, which confirms the capability of degrading organelles by ATTECs and provides potential new strategies in the intervention of mitochondria-related disorders.

Keywords:  Autophagy-tethering compounds; Chimera compound; Lysosome; Neurodegenerative diseases; TSPO; Targeted mitochondrial degradation

DOI:  https://doi.org/10.1016/j.scib.2023.10.021
J Cell Physiol. 2023 Nov 09.

NDP52 SUMOylation contributes to low-dose X-rays-induced cardiac hypertrophy through PINK1/Parkin-mediated mitophagy via MUL1/SUMO2 signalling.

Anbo Gao, Mengjie Wang, Xing Tang, Gangqing Shi, Kai Hou, Jinren Fang, Linlin Zhou, Hong Zhou, Weimin Jiang, Yukun Li, Fan Ouyang.

  Radiation-induced heart damage caused by low-dose X-rays has a significant impact on tumour patients' prognosis, with cardiac hypertrophy being the most severe noncarcinogenic adverse effect. Our previous study demonstrated that mitophagy activation promoted cardiac hypertrophy, but the underlying mechanisms remained unclear. In the present study, PARL-IN-1 enhanced excessive hypertrophy of cardiomyocytes and exacerbated mitochondrial damage. Isobaric tags for relative and absolute quantification-based quantitative proteomics identified NDP52 as a crucial target mediating cardiac hypertrophy induced by low-dose X-rays. SUMOylation proteomics revealed that the SUMO E3 ligase MUL1 facilitated NDP52 SUMOylation through SUMO2. Co-IP coupled with LC-MS/MS identified a critical lysine residue at position 262 of NDP52 as the key site for SUMO2-mediated SUMOylation of NDP52. The point mutation plasmid NDP52K262R inhibited mitophagy under MUL1 overexpression, as evidenced by inhibition of LC3 interaction with NDP52, PINK1 and LAMP2A. A mitochondrial dissociation study revealed that NDP52K262R inhibited PINK1 targeting to endosomes early endosomal marker (EEA1), late/lysosome endosomal marker (LAMP2A) and recycling endosomal marker (RAB11), and laser confocal microscopy confirmed that NDP52K262R impaired the recruitment of mitochondria to the autophagic pathway through EEA1/RAB11 and ATG3, ATG5, ATG16L1 and STX17, but did not affect mitochondrial delivery to lysosomes via LAMP2A for degradation. In conclusion, our findings suggest that MUL1-mediated SUMOylation of NDP52 plays a crucial role in regulating mitophagy in the context of low-dose X-ray-induced cardiac hypertrophy. Two hundred sixty-second lysine of NDP52 is identified as a key SUMOylation site for low-dose X-ray promoting mitophagy activation and cardiac hypertrophy. Collectively, this study provides novel implications for the development of therapeutic strategies aimed at preventing the progression of cardiac hypertrophy induced by low-dose X-rays.

Keywords:  MUL1; NDP52; PINK1/Parkin; SUMOylation; mitophagy; radiation-induced heart damage

DOI:  https://doi.org/10.1002/jcp.31145
J Mol Evol. 2023 Nov 04.

Post-Subfunctionalization Functions of HIF-1αA and HIF-1αB in Cyprinid Fish: Fine-Tuning Mitophagy and Apoptosis Regulation Under Hypoxic Stress.

Wei Chi, Juanjuan Fu, Chris J Martyniuk, Jiangyong Wang, Libin Zhou.

  Hypoxia-inducible factor 1 (HIF-1) is a crucial transcriptional factor that can restore oxygen balance in the body by regulating multiple vital activities. Two HIF-1α copies were retained in cyprinid fish after experiencing a teleost-specific genome duplication. How the "divergent collaboration" of HIF-1αA and HIF-1αB proceeds in regulating mitophagy and apoptosis under hypoxic stress in cells of cyprinid fish remains unclear. In this study, zebrafish HIF-1αA/B expression plasmids were constructed and transfected into the epithelioma papulosum cyprini cells and were subjected to hypoxic stress. HIF-1αA induced apoptosis through promoting ROS generation and mitochondrial depolarization when cells were subjected to oxygen deficiency. Conversely, HIF-1αB was primarily responsible for mitophagy induction, prompting ATP production to mitigate apoptosis. HIF-1αA did not induce mitophagy in the mitochondria and lysosomes co-localization assay but it was involved in the regulation of different mitophagy pathways. Over-expression of HIF-1αA increased the expression of bnip3, fundc1, Beclin1, and foxo3, suggesting it has a dual role in mitochondrial autophagy and cell death. Each duplicated copy also experienced functional divergence and target shifting in the regulation of complexes in the mitochondrial electron transport chain (ETC). Our findings shed light on the post-subfunctionalization function of HIF-1αA and HIF-1αB in zebrafish to fine-tune regulation of mitophagy and apoptosis following hypoxia exposure.

Keywords:  HIF-1α; Hypoxia; Mitophagy; ROS; Subfunctionalization

DOI:  https://doi.org/10.1007/s00239-023-10138-9
Int J Biol Sci. 2023 ;19(16): 5145-5159

PTEN-induced kinase 1 exerts protective effects in diabetic kidney disease by attenuating mitochondrial dysfunction and necroptosis.

Min-Ji Sung, Hyun-Ju An, Min Heui Ha, Seon Hwa Park, Hye Yun Jeong, Jihyun Baek, Sang Ho Lee, Yu Ho Lee, So-Young Lee.

  Mitochondrial dysfunction plays a pivotal role in diabetic kidney disease initiation and progression. PTEN-induced serine/threonine kinase 1 (PINK1) is a core organizer of mitochondrial quality control; however, its function in diabetic kidney disease remains controversial. Here, we aimed to investigate the pathophysiological roles of PINK1 in diabetic tubulopathy, focusing on its effects on mitochondrial homeostasis and tubular cell necroptosis, which is a specialized form of regulated cell death. PINK1-knockout mice showed more severe diabetes-induced tubular injury, interstitial fibrosis, and albuminuria. The expression of profibrotic cytokines significantly increased in the kidneys of diabetic Pink1-/- mice, which eventually culminated in aggravated interstitial fibrosis. Additionally, the knockdown of PINK1 in HKC-8 cells upregulated the fibrosis-associated proteins, and these effects were rescued by PINK1 overexpression. PINK1 deficiency was also associated with exaggerated hyperglycemia-induced mitochondrial dysfunction and defective mitophagic activity, whereas PINK1 overexpression ameliorated these negative effects and restored mitochondrial homeostasis. Mitochondrial reactive oxygen species triggered tubular cell necroptosis under hyperglycemic conditions, which was aggravated by PINK1 deficiency and improved by its overexpression. In conclusion, PINK1 plays a pivotal role in suppressing mitochondrial dysfunction and tubular cell necroptosis under high glucose conditions and exerts protective effects in diabetic kidney disease.

Keywords:  PINK1, diabetic kidney disease; diabetic tubulopathy, mitochondria, necroptosis

DOI:  https://doi.org/10.7150/ijbs.83906
J Appl Physiol (1985). 2023 Nov 09.

Mitophagy-dependent Cardioprotection of Resistance Training on Heart Failure.

Chen Guo, Rui-Yun Wu, Jia-Hao Dou, Shou-Fang Song, Xue-Lu Sun, Yi-Wei Hu, Fan-Shun Guo, Jia Wei, Lin Lin, Jin Wei.

  Resistance exercise is an indispensable mode of exercise rehabilitation for heart failure. Here we elucidate the cardiac effects of resistance training alone or combined with different aerobic trainings on heart failure and explore the critical regulation of mitophagy. The chronic heart failure model was constructed by transverse aortic constriction surgery, followed by 8 weeks of resistance training (RT), moderate-intensity continuous training combined with resistance training (MRT), and high-intensity interval training combined with resistance training (HRT), and subsequently analyzed the changes of maximum load, cardiac structure and function, and myocardial mitophagic activity. The role and signaling of mitophagy in exercise protection of heart failure were investigated by knockdown of Hif1α and Parkin genes in primary neonatal cardiomyocytes. RT and especially MRT improved maximum load (P < 0.0001), myocardial morphology and fibrosis (P < 0.0001), reduced left ventricular diameter and enhanced left ventricular systolic function (P < 0.01), and enhanced myocardial mitophagic activity and HIF1α expression (P < 0.05) in heart failure mice. But HRT had no obvious protective effect on ventricular diameter and function or mitophagy. The abilities of exercise stimulation to regulate reactive oxygen species, adenosine triphosphate, and brain natriuretic peptide were impaired after knockdown of Hif1α and Parkin genes inhibited mitophagy in failing cardiomyocytes (P < 0.05). Different exercise modalities provide discrepant cardiovascular effects on heart failure, and MRT exhibits optimal protection. The HIF1α-Parkin-mitophagy pathway is involved in the protection and regulation of exercise on heart failure.

Keywords:  Resistance training; heart failure; mitophagy

DOI:  https://doi.org/10.1152/japplphysiol.00674.2023
Chin J Physiol. 2023 Sep-Oct;66(5):66(5): 351-358

Reducing myocardial infarction by combination of irisin and Dendrobium nobile Lindl through inhibiting nod-like receptor protein-3-related pyroptosis and activating PINK1/Parkin-mitophagy during aging.

Chen Ding, Chaofeng Zhang.

  Aging, a crucial risk factor for ischemic heart disease, has negative impacts on cardioprotective mechanisms. As such, there is still an unmet requirement to explore potential therapies for improving the outcomes of myocardial ischemia/reperfusion (IR) injury in elderly subjects. Here, we aimed to confirm the cardioprotective function of irisin/Dendrobium nobile Lindl (DNL) combination therapy against myocardial IR injury in aged rats, with a focus on the involvement of pyroptosis and mitophagy. Male aged Wistar rats (22-24 months old, 400-450 g; n = 54) underwent myocardial IR or sham surgery. Before IR operation, rats were pretreated with irisin (0.5 mg/kg, intraperitoneally) and/or DNL (80 mg/kg, orally) for 1 or 4 weeks, respectively, at corresponding groups. Cardiac function, lactate dehydrogenase (LDH) and cardiac-specific isoform of troponin-I (cTn-I) levels, the expression of proteins involved in pyroptosis (nod-like receptor protein-3 (NLRP3), apoptosis-associated speck-like protein, c-caspase-1, and GSDMD-N) and mitophagy (PINK1 and Parkin), and pro-inflammatory cytokines levels were evaluated after 24 h of reperfusion. Irisin/DNL combined therapy significantly restored cardiac function and decreased LDH and cTn-I levels. It also downregulated pyroptosis-related proteins, upregulated PINK1 and Parkin, and decreased pro-inflammatory cytokines secretion. Pretreatment with Mdivi-1, as mitophagy inhibitor, abolished the cardioprotective action of dual therapy. This study revealed the cardioprotective effects of irisin/DNL combination therapy against IR-induced myocardial injury in aged rats, and also showed that the mechanism might be associated with suppression of NLRP3-related pyroptosis through enhancing the activity of the PINK1/Parkin mitophagy. This combination therapy is worthy of further detailed studies due to its potential to alleviate myocardial IR injury upon aging.

Keywords:  Aging; Dendrobium nobile Lindl; irisin; mitophagy; myocardial ischemia/reperfusion injury; pyroptosis

DOI:  https://doi.org/10.4103/cjop.CJOP-D-23-00032
Biomed Pharmacother. 2023 Nov 07. pii: S0753-3322(23)01650-5. [Epub ahead of print]169 115852

Effects of dapagliflozin monotherapy and combined aerobic exercise on skeletal muscle mitochondrial quality control and insulin resistance in type 2 diabetes mellitus rats.

Liangzhi Zhang, Hengjun Lin, Xudong Yang, Jipeng Shi, Xiusheng Sheng, Lifeng Wang, Ting Li, Helong Quan, Xia Zhai, Wei Li.

  Type 2 diabetes mellitus (T2DM) is a prevalent, chronic metabolic disease. Sodium-glucose cotransporter-2 (SGLT2) inhibitors and aerobic exercise (AE) have shown promise in mitigating insulin resistance (IR) and T2DM. This study investigated the effects of dapagliflozin (Dapa) monotherapy and combined AE on mitochondrial quality control (MQC) in skeletal muscle and IR in T2DM rats. T2DM rats, induced by a high-fat diet/streptozotocin model, were randomly assigned to the following groups: T2DM+vehicle group (DMV), T2DM rats treated with Dapa (DMDa, 10 mg/kg/d), T2DM rats subjected to combined Dapa treatment and AE (DMDa+AE), and the standard control group (CON). Blood and skeletal muscle samples were collected after 6 weeks of intragastric administration and treadmill exercise. The results showed that DMDa monotherapy could reduce the accumulation of white adipose tissue and skeletal muscle lipid droplets and improve HOMA-IR. While the combined AE led to further reductions in subcutaneous white adipose tissue and fasting glucose levels, it did not confer additional benefits in terms of HOMA-IR. Furthermore, Dapa monotherapy enhanced skeletal muscle mitochondrial biogenesis (PGC-1α, NRF1, TFAM, and COX IV), mitochondrial dynamics (OPA1, DRP1, and MFN2), and mitophagy (PGAM5 and PINK1) related protein levels. Nevertheless, the combination of Dapa with AE treatment did not yield an additive effect. In conclusion, this study highlights the potential of SGLT2 inhibitors, specifically Dapa, in ameliorating IR and maintaining MQC in skeletal muscle in rats with T2DM. However, combined AE did not produce an additive effect, indicating the need for further research.

Keywords:  Aerobic exercise; Dapagliflozin; Insulin resistance; Mitochondrial quality control; Skeletal muscle; Type 2 diabetes mellitus

DOI:  https://doi.org/10.1016/j.biopha.2023.115852
J Gene Med. 2023 Nov 07. e3617

Erxian Decoction-induced serum exosomes slowed bone marrow mesenchymal stem cell senescence through mitophagy.

Haoqiang Huang, Yinhua Qian, Ye Feng, Yitao Wang, Pingkang Qian, Feng Xu, Qing Wang.

   OBJECTIVE: Erxian Decoction (EXD) is traditionally employed in the treatment of menopausal syndromes, although its underlying mechanisms remain largely undefined. Given that the senescence of bone marrow mesenchymal stem cells (BMSCs) is intertwined with organismal aging and associated diseases, this study endeavored to elucidate the influence of EXD on aging BMSCs and uncover the mechanisms through which EXD impedes BMSC senescence.
METHODS: Initially, we probed the anti-senescent mechanisms of EXD on BMSCs via network pharmacology. We subsequently isolated and identified exosomes from the serum of EXD-fed rats (EXD-Exos) and administered these to H2 O2 -induced aging BMSC. Assays were conducted to assess BMSC senescence indicators and markers pertinent to mitochondrial autophagy. Treatments with mitophagy inhibitors and activators were then employed to substantiate our findings.
RESULTS: Protein-protein interaction (PPI) network analyses spotlighted AKT1, TP53, TNF, JUN, VEGFA, IL6, CASP3 and EGFR as focal targets. Gene Ontology and Kyoto Encylcopedia of Genes and Genomes pathway analyses underscored oxidative stress, mitophagy and cell proliferation as pivotal processes. Our cellular assays ascertained that EXD-Exos mitigated H2 O2 -induced senescence phenotypes in BMSCs. Moreover, EXD-Exos ameliorated disrupted mitophagy in BMSCs, as evidenced by enhanced cellular membrane potential and diminished reactive oxygen species levels. Intriguingly, EXD-Exos also preserved the osteogenic differentiation potential of BMSCs while curtailing their adipogenic propensity.
CONCLUSION: Our findings compellingly suggest that EXD counteracts BMSC senescence by fostering mitophagy.

Keywords:  BMSC; Erxian Decoction; mitophagy; osteogenic differentiation; senescence; serum exosomes

DOI:  https://doi.org/10.1002/jgm.3617
J Exp Clin Cancer Res. 2023 Nov 09. 42(1): 295

PINK1-PTEN axis promotes metastasis and chemoresistance in ovarian cancer via non-canonical pathway.

Fang Zheng, Jiamin Zhong, Kelie Chen, Yu Shi, Fang Wang, Shengchao Wang, Song Tang, Xiaoyu Yuan, Zhangjin Shen, Sangsang Tang, Dajing Xia, Yihua Wu, Weiguo Lu.

   BACKGROUND: Ovarian cancer is commonly associated with a poor prognosis due to metastasis and chemoresistance. PINK1 (PTEN-induced kinase 1) is a serine/threonine kinase that plays a crucial part in regulating various physiological and pathophysiological processes in cancer cells.
METHODS: The ATdb database and "CuratedOvarianData" were used to evaluate the effect of kinases on ovarian cancer survival. The gene expression in ovarian cancer cells was detected by Western blot and quantitative real-time PCR. The effects of gene knockdown or overexpression in vitro were evaluated by wound healing assay, cell transwell assay, immunofluorescence staining, immunohistochemistry, and flow cytometry analysis. Mass spectrometry analysis, protein structure analysis, co-immunoprecipitation assay, nuclear-cytoplasmic separation, and in vitro kinase assay were applied to demonstrate the PINK1-PTEN (phosphatase and tensin homolog) interaction and the effect of this interaction. The metastasis experiments for ovarian cancer xenografts were performed in female BALB/c nude mice.
RESULTS: PINK1 was strongly associated with a poor prognosis in ovarian cancer patients and promoted metastasis and chemoresistance in ovarian cancer cells. Although the canonical PINK1/PRKN (parkin RBR E3 ubiquitin protein ligase) pathway showed weak effects in ovarian cancer, PINK1 was identified to interact with PTEN and phosphorylate it at Serine179. Remarkably, the phosphorylation of PTEN resulted in the inactivation of the phosphatase activity, leading to an increase in AKT (AKT serine/threonine kinase) activity. Moreover, PINK1-mediated phosphorylation of PTEN impaired the nuclear import of PTEN, thereby enhancing the cancer cells' ability to resist chemotherapy and metastasize.
CONCLUSIONS: PINK1 interacts with and phosphorylates PTEN at Serine179, resulting in the activation of AKT and the inhibition of PTEN nuclear import. PINK1 promotes ovarian cancer metastasis and chemotherapy resistance through the regulation of PTEN. These findings offer new potential therapeutic targets for ovarian cancer management.

Keywords:  Chemoresistance; Metastasis; Ovarian cancer; PINK1; PTEN; Phosphorylation

DOI:  https://doi.org/10.1186/s13046-023-02823-w