bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2024–03–24
fiveteen papers selected by
Gavin McStay, Liverpool John Moores University
  1. Integrating the response to stressed mitochondria.
  2. The phospholipids cardiolipin and phosphatidylethanolamine differentially regulate MDC biogenesis.
  3. Imbalance of mitochondrial fusion in peripheral blood mononuclear cells is associated with liver fibrosis in patients with metabolic dysfunction-associated steatohepatitis.
  4. Genetic and pharmacological targeting of XBP1 alleviates hepatic ischemia reperfusion injury by enhancing FoxO1-dependent mitophagy.
  5. Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons.
  6. Quadriceps muscle atrophy after non-invasive anterior cruciate ligament injury: evidence linking to autophagy and mitophagy.
  7. The SCF-FBW7β E3 ligase mediates ubiquitination and degradation of the serine/threonine protein kinase PINK1.
  8. The crude extract obtained from Cinnamomum macrostemon Hayata regulates oxidative stress and mitophagy in keratinocytes.
  9. YME1L-mediated mitophagy protects renal tubular cells against cellular senescence under diabetic conditions.
  10. miR-218-5p and doxorubicin combination enhances anticancer activity in breast cancer cells through Parkin-dependent mitophagy inhibition.
  11. AMPK and insulin control the switch between mitochondrial hitchhiking of Pink1 mRNA and mitophagy in neurons.
  12. Synchronized assembly of the oxidative phosphorylation system controls mitochondrial respiration in yeast.
  13. Future perspectives on the roles of mitochondrial dynamics in the heart in obesity and aging.
  14. NPC1 is required for postnatal islet β cell differentiation by maintaining mitochondria turnover.
  15. Revolutionizing cellular energy: The convergence of mitochondrial dynamics and delivery technologies.
  1. Mol Cell. 2024 Mar 21. pii: S1097-2765(24)00168-0. [Epub ahead of print]84(6): 995-997
    Integrating the response to stressed mitochondria.
    Elliot Dine, Richard J Youle.
      Chakrabarty et al.1 demonstrate that phospho-EIF2α (pEIF2α), the translation initiation factor that mediates the integrated stress response (ISR), is necessary and sufficient for the autophagic degradation of mitochondria following the addition of mitochondrial stressors.
    DOI:  https://doi.org/10.1016/j.molcel.2024.02.026
  2. J Cell Biol. 2024 May 06. pii: e202302069. [Epub ahead of print]223(5):
    The phospholipids cardiolipin and phosphatidylethanolamine differentially regulate MDC biogenesis.
    Tianyao Xiao, Alyssa M English, Zachary N Wilson, J Alan Maschek, James E Cox, Adam L Hughes.
      Cells utilize multiple mechanisms to maintain mitochondrial homeostasis. We recently characterized a pathway that remodels mitochondria in response to metabolic alterations and protein overload stress. This remodeling occurs via the formation of large membranous structures from the mitochondrial outer membrane called mitochondrial-derived compartments (MDCs), which are eventually released from mitochondria and degraded. Here, we conducted a microscopy-based screen in budding yeast to identify factors that regulate MDC formation. We found that two phospholipids, cardiolipin (CL) and phosphatidylethanolamine (PE), differentially regulate MDC biogenesis. CL depletion impairs MDC biogenesis, whereas blocking mitochondrial PE production leads to constitutive MDC formation. Additionally, in response to metabolic MDC activators, cellular and mitochondrial PE declines, and overexpressing mitochondrial PE synthesis enzymes suppress MDC biogenesis. Altogether, our data indicate a requirement for CL in MDC biogenesis and suggest that PE depletion may stimulate MDC formation downstream of MDC-inducing metabolic stress.
    DOI:  https://doi.org/10.1083/jcb.202302069
  3. Heliyon. 2024 Mar 30. 10(6): e27557
    Imbalance of mitochondrial fusion in peripheral blood mononuclear cells is associated with liver fibrosis in patients with metabolic dysfunction-associated steatohepatitis.
    Thanaput Kunlayawutipong, Nattayaporn Apaijai, Kanokkan Tepmalai, Sarawut Kongkarnka, Apinya Leerapun, Kanokporn Pinyopornpanish, Atiwat Soontornpun, Siriporn C Chattipakorn, Nipon Chattipakorn, Kanokwan Pinyopornpanish.
      Mitochondrial dysfunction and inflammation contribute to the pathophysiology of metabolic dysfunction-associated steatohepatitis (MASH). This study aims to evaluate the potential association between mitochondrial dynamics and cell death markers from peripheral blood mononuclear cells (PBMCs) and the presence of MASH with significant liver fibrosis among metabolic dysfunction-associated steatotic liver disease (MASLD) patients. Consecutive patients undergoing bariatric surgery from January to December 2022 were included. Patients with histologic steatosis were classified into MASH with significant fibrosis (F2-4) group or MASLD/MASH without significant fibrosis group (F0-1). Mitochondrial dynamic proteins and cell death markers were extracted from PBMCs. A total of 23 MASLD/MASH patients were included (significant fibrosis group, n = 7; without significant fibrosis group, n = 16). Of the mitochondrial dynamics and cell death markers evaluated, OPA1 protein, a marker of mitochondrial fusion is higher in MASH patients with significant fibrosis compared to those without (0.861 ± 0.100 vs. 0.560 ± 0.260 proportional to total protein, p = 0.001). Mitochondrial fusion/fission (OPA1/DRP1) ratio is significantly higher in MASH patients with significant fibrosis (1.072 ± 0.307 vs. 0.634 ± 0.313, p = 0.009). OPA1 (per 0.01 proportional to total protein) was associated with the presence of significant liver fibrosis with an OR of 1.08 (95%CI, 1.01-1.15, p = 0.035), and adjusted OR of 1.10 (95%CI, 1.00-1.21, p = 0.042). OPA1 from PBMCs is associated with MASH and substantial fibrosis. Future studies should explore if OPA1 could serve as a novel non-invasive liver fibrosis marker.
    Keywords:  Liver cirrhosis; Mitochondria; Non-alcoholic fatty liver disease
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e27557
  4. Transl Res. 2024 Mar 15. pii: S1931-5244(24)00051-3. [Epub ahead of print]
    Genetic and pharmacological targeting of XBP1 alleviates hepatic ischemia reperfusion injury by enhancing FoxO1-dependent mitophagy.
    Baicheng Kuang, Mengqin Wang, Hao Yan, Qin Jiang, Zhiheng Wang, Haiqiang Ni, Shuaiheng Hou, Xuan Peng, Shiqi Gu, Yuanyuan Zhao, Tongwen Ou, Nianqiao Gong.
      Hepatic ischemia reperfusion (I/R) injury is a common clinical complication. X-box binding protein 1 (XBP1), as a critical regulator of the endoplasmic reticulum stress, has been implicated in a variety of diseases. In this study, we aimed to investigate the effects and the underlying mechanism of XBP1 in the progression of hepatic I/R injury. Hepatocyte-specific XBP1 knockout mice, multiple viral delivery systems and specific pharmacological inhibitors were applied in vivo in a partial hepatic I/R injury mouse model and in vitro in a cell model of hypoxia-reoxygenation (H/R) injury. Mitophagy and autophagic flux were evaluated and fluorescence resonance energy transfer (FRET) as well as immunoprecipitation were performed. The results demonstrated that reperfusion for 6 h represented a critical timepoint in hepatic I/R injury and resulted in significant intracellular mitochondrial dysfunction; led to the breakdown of hepatocytes accompanied by the highest expression levels of XBP1. Hepatocyte-specific XBP1 knockout alleviated hepatic I/R injury via enhanced mitophagy, as demonstrated by the reduction in hepatocellular damage/necrosis and increased expression of mitophagy markers. Mechanistically, XBP1 interacted with FoxO1 directly and catalyzed the ubiquitination of FoxO1 for proteasomal degradation. Targeting XBP1 by genetic or pharmacological techniques potentiated the protein levels of FoxO1, further promoting the activity of the PINK1/Parkin signaling pathway, thus augmenting mitophagy and exerting hepatoprotective effects upon I/R injury. In conclusion, the inhibition of XBP1 potentiated FoxO1-mediated mitophagy in hepatic I/R injury. Specific genetic and pharmacological treatment targeting XBP1 in the perioperative 6 h prior to reperfusion exerted beneficial effects, thus providing a novel therapeutic approach.
    Keywords:  FoxO1; Hepatic I/R injury; Mitochondria; Mitophagy; XBP1
    DOI:  https://doi.org/10.1016/j.trsl.2024.03.006
  5. Nat Metab. 2024 Mar 19.
    Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons.
    J Tabitha Hees, Simone Wanderoy, Jana Lindner, Marlena Helms, Hariharan Murali Mahadevan, Angelika B Harbauer.
      Mitochondrial quality control failure is frequently observed in neurodegenerative diseases. The detection of damaged mitochondria by stabilization of PTEN-induced kinase 1 (PINK1) requires transport of Pink1 messenger RNA (mRNA) by tethering it to the mitochondrial surface. Here, we report that inhibition of AMP-activated protein kinase (AMPK) by activation of the insulin signalling cascade prevents Pink1 mRNA binding to mitochondria. Mechanistically, AMPK phosphorylates the RNA anchor complex subunit SYNJ2BP within its PDZ domain, a phosphorylation site that is necessary for its interaction with the RNA-binding protein SYNJ2. Notably, loss of mitochondrial Pink1 mRNA association upon insulin addition is required for PINK1 protein activation and its function as a ubiquitin kinase in the mitophagy pathway, thus placing PINK1 function under metabolic control. Induction of insulin resistance in vitro by the key genetic Alzheimer risk factor apolipoprotein E4 retains Pink1 mRNA at the mitochondria and prevents proper PINK1 activity, especially in neurites. Our results thus identify a metabolic switch controlling Pink1 mRNA localization and PINK1 activity via insulin and AMPK signalling in neurons and propose a mechanistic connection between insulin resistance and mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s42255-024-01007-w
  6. Front Physiol. 2024 ;15 1341723
    Quadriceps muscle atrophy after non-invasive anterior cruciate ligament injury: evidence linking to autophagy and mitophagy.
    Sung Gi Noh, Ahram Ahn, Steven M Davi, Lindsey K Lepley, Oh Sung Kwon.
      Introduction: Anterior cruciate ligament (ACL) injury is frequently accompanied by quadriceps muscle atrophy, a process closely linked to mitochondrial health and mitochondria-specific autophagy. However, the temporal progression of key quadricep atrophy-mediating events following ACL injury remains poorly understood. To advance our understanding, we conducted a longitudinal study to elucidate key parameters in quadriceps autophagy and mitophagy. Methods: Long-Evans rats were euthanized at 7, 14, 28, and 56 days after non-invasive ACL injury that was induced via tibial compression overload; controls were not injured. Vastus lateralis muscle was extracted, and subsequent immunoblotting analysis was conducted using primary antibodies targeting key proteins involved in autophagy and mitophagy cellular processes. Results: Our findings demonstrated dynamic changes in autophagy and mitophagy markers in the quadriceps muscle during the recovery period after ACL injury. The early response to the injury was characterized by the induction of autophagy at 14 days (Beclin1), indicating an initial cellular response to the injury. Subsequently, at 14 days we observed increase in the elongation of autophagosomes (Atg4B), suggesting a potential remodeling process. The autophagosome flux was also augmented between 14- and 28 days (LC3-II/LC3-I ratio and p62). Notably, at 56 days, markers associated with the elimination of damaged mitochondria were elevated (PINK1, Parkin, and VDAC1), indicating a possible ongoing cellular repair and restoration process. Conclusion: These data highlight the complexity of muscle recovery after ACL injury and underscore the overlooked but crucial role of autophagy and mitophagy in promoting the recovery process.
    Keywords:  ACL injury; autophagy; mitophagy; muscle atrophy; vastus lateralis muscle
    DOI:  https://doi.org/10.3389/fphys.2024.1341723
  7. J Biol Chem. 2024 Mar 18. pii: S0021-9258(24)01693-4. [Epub ahead of print] 107198
    The SCF-FBW7β E3 ligase mediates ubiquitination and degradation of the serine/threonine protein kinase PINK1.
    Seo Jeong Jeon, Kwang Chul Chung.
      Understanding the mechanisms that govern the stability of functionally crucial proteins is essential for various cellular processes, development, and overall cell viability. Disturbances in protein homeostasis are linked to the pathogenesis of neurodegenerative diseases (NDDs). PINK1, a protein kinase, plays a significant role in mitochondrial quality control and cellular stress response, and its mutated forms lead to early-onset Parkinson's disease (PD). Despite its importance, the specific mechanisms regulating PINK1 protein stability have remained unclear. This study reveals a cytoplasmic interaction between PINK1 and FBW7β in mammalian cells. FBW7β, a component of the Skp1-Cullin-1-F-box protein (SCF) complex-type ubiquitin ligase, is instrumental in recognizing substrates. Our findings demonstrate that FBW7β regulates PINK1 stability through the SCF complex and the proteasome pathway. It facilitates the K48-linked polyubiquitination of PINK1, marking it for degradation. When FBW7 is absent, PINK1 accumulates, leading to heightened mitophagy triggered by carbonyl cyanide 3-chlorophenylhydrazone treatment. Moreover, exposure to the toxic compound staurosporine accelerates PINK1 degradation via FBW7β, correlating with increased cell death. This study unravels the intricate mechanisms controlling PINK1 protein stability and sheds light on the novel role of FBW7β. These findings deepen our understanding of PINK1-related pathologies and potentially pave the way for therapeutic interventions.
    Keywords:  FBW7; Neurodegenerative diseases; PINK1; Parkinson's disease; Proteasomal degradation; SCF complex; Ubiquitination
    DOI:  https://doi.org/10.1016/j.jbc.2024.107198
  8. Biosci Biotechnol Biochem. 2024 Mar 20. pii: zbae022. [Epub ahead of print]
    The crude extract obtained from Cinnamomum macrostemon Hayata regulates oxidative stress and mitophagy in keratinocytes.
    Yung-Shun Su, Ming-Jen Cheng, Aij-Lie Kwan, Shu-Ping Huang, Yu-Chang Tyan, Chee-Yin Chai, Bin Huang.
      Four ethanol fractionated crude extracts (EFCE. A-D) purified from the leaves of Cinnamomum macrostemon Hayata were screened for anti-oxidative effects and mitochondrial function in HaCaT cells. The higher cell viability indicated that EFCE. C was mildly toxic. Under the treatment of 50 ng/mL EFCE. C, the H2O2-induced cytosolic and mitochondrial ROS levels were reduced as well as the H2O2-impaired cell viability, mitochondrial membrane potential (MMP), ATP production and mitochondrial mass. The conversion of globular mitochondria to tubular mitochondria coincident to EFCE. C-restored mitochondrial function. The mitophagy activator rapamycin showed similar effects as EFCE. C in recovering the H2O2-impaired cell viability, MMP, ATP production, mitochondrial mass, and also mitophagic proteins such as PINK 1, Parkin, LC3 II, and biogenesis protein PGC-1α. We thereby propose the application of EFCE. C in the prevention of oxidative stress in skin cells.
    Keywords:  Cinnamon; keratinocyte; mitophagy; oxidative stress; rapamycin
    DOI:  https://doi.org/10.1093/bbb/zbae022
  9. Biol Res. 2024 Mar 17. 57(1): 10
    YME1L-mediated mitophagy protects renal tubular cells against cellular senescence under diabetic conditions.
    Yuanyuan Luo, Lingxiao Zhang, Ning Su, Lerong Liu, Tongfeng Zhao.
       BACKGROUND: The senescence of renal tubular epithelial cells (RTECs) is crucial in the progression of diabetic kidney disease (DKD). Accumulating evidence suggests a close association between insufficient mitophagy and RTEC senescence. Yeast mitochondrial escape 1-like 1 (YME1L), an inner mitochondrial membrane metalloprotease, maintains mitochondrial integrity. Its functions in DKD remain unclear. Here, we investigated whether YME1L can prevent the progression of DKD by regulating mitophagy and cellular senescence.
    METHODS: We analyzed YME1L expression in renal tubules of DKD patients and mice, explored transcriptomic changes associated with YME1L overexpression in RTECs, and assessed its impact on RTEC senescence and renal dysfunction using an HFD/STZ-induced DKD mouse model. Tubule-specific overexpression of YME1L was achieved through the use of recombinant adeno-associated virus 2/9 (rAAV 2/9). We conducted both in vivo and in vitro experiments to evaluate the effects of YME1L overexpression on mitophagy and mitochondrial function. Furthermore, we performed LC-MS/MS analysis to identify potential protein interactions involving YME1L and elucidate the underlying mechanisms.
    RESULTS: Our findings revealed a significant decrease in YME1L expression in the renal tubules of DKD patients and mice. However, tubule-specific overexpression of YME1L significantly alleviated RTEC senescence and renal dysfunction in the HFD/STZ-induced DKD mouse model. Moreover, YME1L overexpression exhibited positive effects on enhancing mitophagy and improving mitochondrial function both in vivo and in vitro. Mechanistically, our LC-MS/MS analysis uncovered a crucial mitophagy receptor, BCL2-like 13 (BCL2L13), as an interacting partner of YME1L. Furthermore, YME1L was found to promote the phosphorylation of BCL2L13, highlighting its role in regulating mitophagy.
    CONCLUSIONS: This study provides compelling evidence that YME1L plays a critical role in protecting RTECs from cellular senescence and impeding the progression of DKD. Overexpression of YME1L demonstrated significant therapeutic potential by ameliorating both RTEC senescence and renal dysfunction in the DKD mice. Moreover, our findings indicate that YME1L enhances mitophagy and improves mitochondrial function, potentially through its interaction with BCL2L13 and subsequent phosphorylation. These novel insights into the protective mechanisms of YME1L offer a promising strategy for developing therapies targeting DKD.
    Keywords:  Cellular senescence; Diabetic kidney disease; Mitophagy; Tubular cell; YME1L
    DOI:  https://doi.org/10.1186/s40659-024-00487-0
  10. Cell Death Discov. 2024 Mar 21. 10(1): 149
    miR-218-5p and doxorubicin combination enhances anticancer activity in breast cancer cells through Parkin-dependent mitophagy inhibition.
    Francesco Davide Naso, Krenare Bruqi, Valeria Manzini, Valerio Chiurchiù, Mara D'Onofrio, Ivan Arisi, Flavie Strappazzon.
      Breast Cancer (BC) is one of the most common tumours, and is known for its ability to develop resistance to chemotherapeutic treatments. Autophagy has been linked to chemotherapeutic response in several types of cancer, highlighting its contribution to this process. However, the role of mitophagy, a selective form of autophagy responsible for damaged mitochondria degradation, in the response to therapies in BC is still unclear. In order to address this point, we analysed the role of mitophagy in the treatment of the most common anticancer drug, doxorubicin (DXR), in different models of BC, such as a luminal A subtype-BC cell line MCF7 cells, cultured in 2-Dimension (2D) or in 3-Dimension (3D), and the triple negative BC (TNBC) cell line MDA-MB-231. Through a microarray analysis, we identified a relationship between mitophagy gene expressions related to the canonical PINK1/Parkin-mediated pathway and DXR treatment in BC cells. Afterwards, we demonstrated that the PINK1/Parkin-dependent mitophagy is indeed induced following DXR treatment and that exogenous expression of a small non-coding RNA, the miRNA-218-5p, known to target mRNA of Parkin, was sufficient to inhibit the DXR-mediated mitophagy in MCF7 and in MDA-MB-231 cells, thereby increasing their sensitivity to DXR. Considering the current challenges involved in BC refractory to treatment, our work could provide a promising approach to prevent tumour resistance and recurrence, potentially leading to the development of an innovative approach to combine mitophagy inhibition and chemotherapy.
    DOI:  https://doi.org/10.1038/s41420-024-01914-7
  11. Nat Metab. 2024 Mar 19.
    AMPK and insulin control the switch between mitochondrial hitchhiking of Pink1 mRNA and mitophagy in neurons.
      
    DOI:  https://doi.org/10.1038/s42255-024-01006-x
  12. Dev Cell. 2024 Mar 18. pii: S1534-5807(24)00110-2. [Epub ahead of print]
    Synchronized assembly of the oxidative phosphorylation system controls mitochondrial respiration in yeast.
    Daiana N Moretti-Horten, Carlotta Peselj, Asli Aras Taskin, Lisa Myketin, Uwe Schulte, Oliver Einsle, Friedel Drepper, Marcin Luzarowski, F-Nora Vögtle.
      Control of protein stoichiometry is essential for cell function. Mitochondrial oxidative phosphorylation (OXPHOS) presents a complex stoichiometric challenge as the ratio of the electron transport chain (ETC) and ATP synthase must be tightly controlled, and assembly requires coordinated integration of proteins encoded in the nuclear and mitochondrial genome. How correct OXPHOS stoichiometry is achieved is unknown. We identify the MitochondrialRegulatory hub for respiratoryAssembly (MiRA) platform, which synchronizes ETC and ATP synthase biogenesis in yeast. Molecularly, this is achieved by a stop-and-go mechanism: the uncharacterized protein Mra1 stalls complex IV assembly. Two "Go" signals are required for assembly progression: binding of the complex IV assembly factor Rcf2 and Mra1 interaction with an Atp9-translating mitoribosome induce Mra1 degradation, allowing synchronized maturation of complex IV and the ATP synthase. Failure of the stop-and-go mechanism results in cell death. MiRA controls OXPHOS assembly, ensuring correct stoichiometry of protein machineries encoded by two different genomes.
    Keywords:  complex stoichiometry; mitochondria; mitoribosome; protein complex assembly; protein import; protein quality control; respiratory chain
    DOI:  https://doi.org/10.1016/j.devcel.2024.02.011
  13. Life Sci. 2024 Mar 14. pii: S0024-3205(24)00164-4. [Epub ahead of print]344 122575
    Future perspectives on the roles of mitochondrial dynamics in the heart in obesity and aging.
    Chayodom Maneechote, Siriporn C Chattipakorn, Nipon Chattipakorn.
      Increasing global obesity rates and an aging population are independently linked to cardiac complications. Consequently, it is crucial to comprehensively understand the mechanisms behind these conditions to advance innovative therapies for age-related diseases. Mitochondrial dysfunction, specifically defects in mitochondrial fission/fusion processes, has emerged as a central regulator of cardiac complications in aging and age-related diseases (e.g., obesity). Since excessive fission and impaired fusion of cardiac mitochondria lead to disruptions in mitochondrial dynamics and cellular metabolism in aging and obesity, modulating mitochondrial dynamics with either fission inhibitors or fusion promoters has offered cardioprotection against these pathological conditions in preclinical models. This review explores the molecular mechanisms governing mitochondrial dynamics as well as the disturbances observed in aging and obesity. Additionally, pharmaceutical interventions that specifically target the processes of mitochondrial fission and fusion are presented and discussed. By establishing a connection between mitochondrial dynamism through fission and fusion and the advancement or mitigation of age-related diseases, particularly obesity, this review provides valuable insights into the progression and potential prevention strategies for such conditions.
    Keywords:  Aging; Cardiovascular disease; Mitochondria; Mitochondrial dynamics; Obesity
    DOI:  https://doi.org/10.1016/j.lfs.2024.122575
  14. Theranostics. 2024 ;14(5): 2058-2074
    NPC1 is required for postnatal islet β cell differentiation by maintaining mitochondria turnover.
    Bei Liu, Duanyi Hua, Linyan Shen, Tingting Li, Zheying Tao, Chenyang Fu, Zhongzheng Tang, Jie Yang, Li Zhang, Aifang Nie, Yiran Jiang, Jiqiu Wang, Yang Li, Yanyun Gu, Guang Ning.
      Rationale: NPC1 is a protein localized on the lysosome membrane regulating intracellular cholesterol transportation and maintaining normal lysosome function. GWAS studies have found that NPC1 variants in T2D was a pancreatic islet expression quantitative trait locus, suggesting a potential role of NPC1 in T2D islet pathophysiology. Methods: Two-week-old Npc1-/- mice and wild type littermates were employed to examine pancreatic β cell morphology and functional changes induced by loss of Npc1. Single cell RNA sequencing was conducted on primary islets. Npc1-/- Min6 cell line was generated using CRISPR/Cas9 gene editing. Seahorse XF24 was used to analyze primary islet and Min6 cell mitochondria respiration. Ultra-high-resolution cell imaging with Lattice SIM2 and electron microscope imaging were used to observe mitochondria and lysosome in primary islet β and Min6 cells. Mitophagy Dye and mt-Keima were used to measure β cell mitophagy. Results: In Npc1-/- mice, we found that β cell survival and pancreatic β cell mass expansion as well as islet glucose induced insulin secretion in 2-week-old mice were reduced. Npc1 loss retarded postnatal β cell differentiation and growth as well as impaired mitochondria oxidative phosphorylation (OXPHOS) function to increase mitochondrial superoxide production, which might be attributed to impaired autophagy flux particularly mitochondria autophagy (mitophagy) induced by dysfunctional lysosome in Npc1 null β cells. Conclusion: Our study revealed that NPC1 played an important role in maintaining normal lysosome function and mitochondria turnover, which ensured establishment of sufficient mitochondria OXPHOS for islet β cells differentiation and maturation.
    Keywords:  NPC1; diabetes; lysosome; mitophagy; β cell differentiation
    DOI:  https://doi.org/10.7150/thno.90946
  15. Mitochondrion. 2024 Mar 17. pii: S1567-7249(24)00031-X. [Epub ahead of print]76 101873
    Revolutionizing cellular energy: The convergence of mitochondrial dynamics and delivery technologies.
    Dilpreet Singh.
      The intersection of mitochondrial dynamics and delivery technologies heralds a paradigm shift in cellular biology and therapeutic intervention. Mitochondrial dynamics, encompassing fusion, fission, transport, and mitophagy, are critical for cellular energy production, signaling, and homeostasis. Dysregulation of these processes is implicated in a myriad of diseases, including neurodegenerative disorders, cardiovascular diseases, and cancer. Concurrently, advances in delivery technologies, such as nanocarriers, targeted delivery systems, and gene editing tools, offer unprecedented opportunities to manipulate mitochondrial function directly. This review synthesizes current knowledge on mitochondrial dynamics, examines recent breakthroughs in targeted delivery methods, and explores their potential convergence to modulate cellular energetics for therapeutic purposes. By integrating insights from biology, chemistry, and bioengineering, this review highlights the innovative approaches being developed to enhance mitochondrial function, underscoring the potential of this convergence to address complex diseases. This interdisciplinary perspective not only broadens our understanding of cellular processes but also paves the way for novel therapeutic strategies, marking a significant step forward in the quest for precision medicine and targeted interventions in mitochondrial-related diseases.
    Keywords:  Delivery; Mitochondria; Personalized medicine; Strategies; Technologies; Therapeutic effect
    DOI:  https://doi.org/10.1016/j.mito.2024.101873
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