bims-tofagi 2023-08-20 papers

on Mitophagy

Issue of 2023–08–20
fiveteen papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea

NLRX1: versatile functions of a mitochondrial NLR protein that controls mitophagy.
When mitophagy dictates the outcome of cellular infection: the case of Brucella abortus.
The mitophagy pathway and its implications in human diseases.
The ubiquitin-like modifier FAT10 covalently modifies HUWE1 and strengthens the interaction of AMBRA1 and HUWE1.
E4 ubiquitin ligase promotes mitofusin turnover and mitochondrial stress response.
Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired.
PPAR-gamma agonist pioglitazone recovers mitochondrial quality control in fibroblasts from PITRM1-deficient patients.
Cardiovascular aging: the mitochondrial influence.
Phagophore closure, autophagosome maturation and autophagosome fusion during macroautophagy in the yeast Saccharomyces cerevisiae.
Choline dehydrogenase interacts with SQSTM1 to activate mitophagy and promote coelomocyte survival in Apostichopus japonicus following Vibrio splendidus infection.
Enhanced Mitophagy in Cholesteatoma Epithelial Cells.
Presenilins and mitochondria-an intriguing link: mini-review.
C-terminal sequence stability profiling in Saccharomyces cerevisiae reveals protective protein quality control pathways.
Prohibitin2/PHB2, Transcriptionally Regulated by GABPA, Inhibits Cell Growth via PRKN/Parkin-dependent Mitophagy in Endometriosis.
Impaired Removal of the Damaged Mitochondria in the Metabolic Memory Phenomenon Associated with Continued Progression of Diabetic Retinopathy.

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
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
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
PLoS One. 2023 ;18(8): e0290002

The ubiquitin-like modifier FAT10 covalently modifies HUWE1 and strengthens the interaction of AMBRA1 and HUWE1.

Stefanie Mueller, Johanna Bialas, Stella Ryu, Nicola Catone, Annette Aichem.

The ubiquitin-like modifier FAT10 is highly upregulated under inflammatory conditions and targets its conjugation substrates to the degradation by the 26S proteasome. This process termed FAT10ylation is mediated by an enzymatic cascade and includes the E1 activating enzyme ubiquitin-like modifier activating enzyme 6 (UBA6), the E2 conjugating enzyme UBA6-specific E2 enzyme 1 (USE1) and E3 ligases, such as Parkin. In this study, the function of the HECT-type ubiquitin E3 ligase HUWE1 was investigated as a putative E3 ligase and/or conjugation substrate of FAT10. Our data provide strong evidence that HUWE1 is FAT10ylated in a UBA6 and FAT10 diglycine-dependent manner in vitro and in cellulo and that the HUWE1-FAT10 conjugate is targeted to proteasomal degradation. Since the mutation of all relevant cysteine residues within the HUWE1 HECT domain did not abolish FAT10 conjugation, a role of HUWE1 as E3 ligase for FAT10ylation is rather unlikely. Moreover, we have identified the autophagy-related protein AMBRA1 as a new FAT10 interaction partner. We show that the HUWE1-FAT10 conjugate formation is diminished in presence of AMBRA1, while the interaction between AMBRA1 and HUWE1 is strengthened in presence of FAT10. This implies a putative interplay of all three proteins in cellular processes such as mitophagy.

DOI: https://doi.org/10.1371/journal.pone.0290002
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
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
Front Pharmacol. 2023 ;14 1220620

PPAR-gamma agonist pioglitazone recovers mitochondrial quality control in fibroblasts from PITRM1-deficient patients.

Alessia Di Donfrancesco, Christian Berlingieri, Marta Giacomello, Chiara Frascarelli, Ana Paula Magalhaes Rebelo, Laurence A Bindoff, Segel Reeval, Paul Renbaum, Filippo M Santorelli, Giulia Massaro, Carlo Viscomi, Massimo Zeviani, Daniele Ghezzi, Emanuela Bottani, Dario Brunetti.

  Introduction: Biallelic variants in PITRM1 are associated with a slowly progressive syndrome characterized by intellectual disability, spinocerebellar ataxia, cognitive decline and psychosis. The pitrilysin metallopeptidase 1 (PITRM1) is a mitochondrial matrix enzyme, which digests diverse oligopeptides, including the mitochondrial targeting sequences (MTS) that are cleaved from proteins imported across the inner mitochondrial membrane by the mitochondrial processing peptidase (MPP). Mitochondrial peptidases also play a role in the maturation of Frataxin, the protein affected in Friedreich's ataxia. Recent studies in yeast indicated that the mitochondrial matrix protease Ste23, which is a homologue of the human insulin-degrading enzyme (IDE), cooperates with Cym1 (homologue of PITRM1) to ensure the proper functioning of the preprotein processing machinery. In humans, IDE could be upregulated by Peroxisome Proliferator-Activated Receptor Gamma (PPARG) agonists. Methods: We investigated preprotein processing, mitochondrial membrane potential and MTS degradation in control and patients' fibroblasts, and we evaluated the pharmacological effect of the PPARG agonist Pioglitazone on mitochondrial proteostasis. Results: We discovered that PITRM1 dysfunction results in the accumulation of MTS, leading to the disruption and dissipation of the mitochondrial membrane potential. This triggers a feedback inhibition of MPP activity, consequently impairing the processing and maturation of Frataxin. Furthermore, we found that the pharmacological stimulation of PPARG by Pioglitazone upregulates IDE and also PITRM1 protein levels restoring the presequence processing machinery and improving Frataxin maturation and mitochondrial function. Discussion: Our findings provide mechanistic insights and suggest a potential pharmacological strategy for this rare neurodegenerative mitochondrial disease.

Keywords:  cerebellar ataxia; mitochondrial disease; neurodegenaration; pioglitazone; proteostasis

DOI:  https://doi.org/10.3389/fphar.2023.1220620
J Cardiovasc Aging. 2023 Jul;pii: 33. [Epub ahead of print]3(3):

Cardiovascular aging: the mitochondrial influence.

Shakti Sagar, Asa B Gustafsson.

  Age-associated cardiovascular disease is becoming progressively prevalent due to the increased lifespan of the population. However, the fundamental mechanisms underlying the aging process and the corresponding decline in tissue functions are still poorly understood. The heart has a very high energy demand and the cellular energy needed to sustain contraction is primarily generated by mitochondrial oxidative phosphorylation. Mitochondria are also involved in supporting various metabolic processes, as well as activation of the innate immune response and cell death pathways. Given the central role of mitochondria in energy metabolism and cell survival, the heart is highly susceptible to the effects of mitochondrial dysfunction. These key organelles have been implicated as underlying drivers of cardiac aging. Here, we review the evidence demonstrating the mitochondrial contribution to the cardiac aging process and disease susceptibility. We also discuss the potential mechanisms responsible for the age-related decline in mitochondrial function.

Keywords:  Aging; heart disease; mitochondria

DOI:  https://doi.org/10.20517/jca.2023.22
FEBS Lett. 2023 Aug 16.

Phagophore closure, autophagosome maturation and autophagosome fusion during macroautophagy in the yeast Saccharomyces cerevisiae.

Claudine Kraft, Fulvio Reggiori.

  Macroautophagy, hereafter referred to as autophagy, is a complex process in which multiple membrane-remodeling events lead to the formation of a cisterna known as the phagophore, which then expands and closes into a double-membrane vesicle termed the autophagosome. During the past decade, enormous progress has been made in understanding the molecular function of the autophagy-related proteins and their role in generating these phagophores. In this Review, we discuss the current understanding of three membrane remodeling steps in autophagy that remain to be largely characterized; namely, the closure of phagophores, the maturation of the resulting autophagosomes into fusion-competent vesicles, and their fusion with vacuoles/lysosomes. Our review will mainly focus on the yeast Saccharomyces cerevisiae, which has been the leading model system for the study of molecular events in autophagy and has led to the discovery of the major mechanistic concepts, which have been found to be mostly conserved in higher eukaryotes.

Keywords:  Atg proteins; Autophagy; PAS; dephosphorylation; phagophore

DOI:  https://doi.org/10.1002/1873-3468.14720
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
Otol Neurotol. 2023 Aug 15.

Enhanced Mitophagy in Cholesteatoma Epithelial Cells.

Quan-Cheng Li, Shu-Qi Wang, Zai-Zai Cao, Shui-Hong Zhou.

HYPOTHESIS: Mitophagy may have a potential role in the pathogenesis of acquired cholesteatoma.
BACKGROUND: Enhanced mitophagy has been proven to be involved in various cancers. However, its role in the pathogenesis of cholesteatoma, which shares some common features with cancer, is controversial. This study investigated mitophagy in cholesteatoma epithelial cells.
METHODS: The autophagy protein markers LC3-II and p62 and mitophagy proteins BNIP3, Parkin, and PINK1 were analyzed in cholesteatoma epithelial cells and external auditory canal epithelium cells by immunoblotting. The results were confirmed by immunohistochemistry. Adenovirus Ad-mCherry-GFP-LC3B and Ad-GFP-LC3B were used to evaluate autophagic activity. Transmission electron microscopy was used to observe and analyze autophagosomes.
RESULTS: LC3-II expression was increased in cholesteatoma cells, whereas soluble and insoluble p62 levels were decreased. The expressions of BNIP3, Parkin, and PINK1 were higher in total protein and mitochondrial protein of cholesteatoma cells compared with normal external auditory canal epithelium cells. Autophagic activity was increased in cholesteatoma cells compared with normal external auditory canal epithelium cells.
CONCLUSION: Mitophagy was enhanced in cholesteatoma epithelial cells and may have a potential role in the pathogenesis of acquired cholesteatoma.

DOI: https://doi.org/10.1097/MAO.0000000000003986
Front Neurosci. 2023 ;17 1249815

Presenilins and mitochondria-an intriguing link: mini-review.

Mark Makarov, Liliia Kushnireva, Michele Papa, Eduard Korkotian.

  This review uncovers the intricate relationship between presenilins, calcium, and mitochondria in the context of Alzheimer's disease (AD), with a particular focus on the involvement of presenilin mutations in mitochondrial dysfunction. So far, it is unclear whether the impairment of mitochondrial function arises primarily from damage inflicted by β-amyloid upon mitochondria or from the disruption of calcium homeostasis due to presenilins dysfunctions. The roles of presenilins in mitophagy, autophagy, mitochondrial dynamics, and many other functions, non-γ-secretase related, also require close attention in future research. Resolution of contradictions in understanding of presenilins cellular functions are needed for new effective therapeutic strategies for AD.

Keywords:  Alzheimer’s disease; mitochondria associated membranes; neurodegeneration; presenilins; spine apparatus

DOI:  https://doi.org/10.3389/fnins.2023.1249815
J Biol Chem. 2023 Aug 16. pii: S0021-9258(23)02194-4. [Epub ahead of print] 105166

C-terminal sequence stability profiling in Saccharomyces cerevisiae reveals protective protein quality control pathways.

Sophia Hasenjäger, Andrea Bologna, Lars-Oliver Essen, Roberta Spadaccini, Christof Taxis.

  Protein quality control (PQC) mechanisms are essential for degradation of misfolded or dysfunctional proteins. An essential part of protein homeostasis is recognition of defective proteins by PQC components and their elimination by the ubiquitin-proteasome system, often concentrating on protein termini as indicators of protein integrity. Changes in amino acid composition of C-terminal ends arise through protein disintegration, alternative splicing or during the translation step of protein synthesis from premature termination or translational stop-codon read-through. We characterized reporter protein stability using light-controlled exposure of random C-terminal peptides (CtPC) in budding yeast revealing stabilizing and destabilizing features of amino acids at positions -5 to -1 of the C-terminus. The (de)stabilization properties of CtPC-degrons depend on amino acid identity, position as well as composition of the C-terminal sequence and are transferable. Evolutionary pressure towards stable proteins in yeast is evidenced by amino acid residues under-represented in cytosolic and nuclear proteins at corresponding C-terminal positions, but over-represented in unstable CtPC-degrons, and vice versa. Furthermore, analysis of translational stop-codon read-through peptides suggested that such extended proteins have destabilizing C-termini. PQC pathways targeting CtPC-degrons involved the ubiquitin-protein ligase Doa10 and the cullin-RING E3 ligase (CRL) SCFDas1. Overall, our data suggest a proteome protection mechanism that targets proteins with unnatural C-termini by recognizing a surprisingly large number of C-terminal sequence variants.

Keywords:  C-terminus; optogenetics; proteasome; protein degradation; protein quality control; proteolysis; ubiquitin-proteasome system

DOI:  https://doi.org/10.1016/j.jbc.2023.105166
Reprod Sci. 2023 Aug 16.

Prohibitin2/PHB2, Transcriptionally Regulated by GABPA, Inhibits Cell Growth via PRKN/Parkin-dependent Mitophagy in Endometriosis.

Yupeng Deng, Tong Lou, Lili Kong, Chongdong Liu.

  Endometriosis (EMS) is a common benign gynecological disease affecting women of reproductive age. It is characterized by abnormal growth of endometrial tissue outside the uterine cavity, resulting in chronic pelvic pain and infertility. Endometrial physiological and pathological processes are intimately connected to autophagy. Mitophagy is an essential selective mode that protects cells from metabolic stress and hypoxia. Mitochondrial autophagy mediated by prohibitin 2 (PHB2) is dependent on the PRKN/Parkin pathway and is involved in numerous human diseases. Uncertainty remains as to whether mitophagy regulation by PHB2 contributes to the occurrence and progression of EMS. This study aims to investigate the mechanism underlying the role of PHB2 in EMS. This study detected the protein and mRNA expression of PHB2 in ectopic and normal endometrial tissues of ovarian EMS, in addition to ectopic endometrial cell line 12Z and endometrial stromal cell line KC02-44D for gene overexpression or knockdown. Cell function experiments and mitochondrial function experiments were conducted to investigate the role of PHB2 in the endometrium. Bioinformatic analysis and experiments were also used to investigate the upstream transcription factors that influence PHB2 expression. PHB2 was downregulated in ectopic endometrium, and PHB2 overexpression inhibited cell proliferation, migration, and invasion and promoted apoptosis. The upregulation of mitophagy markers, including Parkin and LC3II/I, and the downregulation of autophagy degradation markers P62 and TOMM20 in EMS suggest that PHB2 may contribute to cell proliferation, migration, invasion, and apoptosis via PRKN/Parkin-mediated mitophagy. Analysis and validation of bioinformatics data revealed that the transcription factor GABPA binds directly to the PHB2 promoter region and controls the transcriptional expression of PHB2. This study investigated the role of PHB2 in the onset of EMS. It inhibits EMS growth via PRKN/Parkin-mediated mitophagy, and GABPA controls the transcriptional disorder of PHB2. This study's findings suggest a novel method for investigating the clinical potential of PHB2 in EMS.

Keywords:  Endometriosis; GABPA; Mitophagy; PHB2; PRKN/Parkin

DOI:  https://doi.org/10.1007/s43032-023-01316-7
Mol Neurobiol. 2023 Aug 18.

Impaired Removal of the Damaged Mitochondria in the Metabolic Memory Phenomenon Associated with Continued Progression of Diabetic Retinopathy.

Renu A Kowluru, Ghulam Mohammad, Jay Kumar.

  Retinopathy fails to halt even after diabetic patients in poor glycemic control try to institute tight glycemic control, suggesting a "metabolic memory" phenomenon, and the experimental models have demonstrated that mitochondria continue to be damaged/dysfunctional, fueling into the vicious cycle of free radicals. Our aim was to investigate the role of removal of the damaged mitochondria in the metabolic memory. Using human retinal endothelial cells (HRECs), incubated in 20 mM D-glucose for 4 days, followed by 5 mM D-glucose for 4 additional days, mitochondrial turnover, formation of mitophagosome, and mitophagy flux were evaluated. Mitophagy was confirmed in a rat model of metabolic memory where the rats were kept in poor glycemic control (blood glucose ~ 400 mg/dl) for 3 months soon after induction of streptozotocin-induced diabetes, followed by 3 additional months of good control (BG < 150 mg/dl). Reversal of high glucose by normal glucose had no effect on mitochondrial turnover and mitophagosome formation, and mitophagy flux remained compromised. Similarly, 3 months of good glycemic control in rats, which had followed 3 months of poor glycemic control, had no effect on mitophagy flux. Thus, poor turnover/removal of the damaged mitochondria, initiated during poor glycemic control, does not benefit from the termination of hyperglycemic insult, and the damaged mitochondria continue to produce free radicals, suggesting the importance of mitophagy in the metabolic memory phenomenon associated with the continued progression of diabetic retinopathy.

Keywords:  Diabetes; Metabolic memory; Mitochondria; Mitophagy; Retinopathy

DOI:  https://doi.org/10.1007/s12035-023-03534-1