Prion diseases are chronic, transmissible, and neurodegenerative disorders that affect both humans and other mammals. Mitophagy is essential for maintaining mitochondrial homeostasis and normal neuronal function. Our previous research show that the PINK1-Parkin-dependent mitophagy pathway is impaired in the PrP106-126 induced prion disease model, yet the underlying downstream mechanisms remain elusive. We report that impaired phosphorylation of ubiquitin at Ser65 diminishes OPTN recruitment to mitochondria, thereby influence mitochondrial translocation of TBK1 and ATG9A, consequently suppresses TBK1 autophosphorylation that depends on the OPTN-ATG9A interaction. As a result, reduction of OPTN phosphorylation dependent on TBK1 inhibits autophagosome formation and ultimately leads to defective mitophagy. Importantly, overexpression of OPTN rescued the mitophagy impairment induced by PrP106-126 and partially restoring mitochondrial morphology and function. Our findings identify OPTN as a critical node, proposing its therapeutic targeting as a strategy to counteract prion disease progression.

Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and prion diseases represent a growing global health crisis. Despite significant research efforts, disease-modifying therapies remain elusive. Immunotherapy, particularly vaccination, offers a promising avenue by leveraging the body's immune system to clear pathological protein aggregates central to these disorders. This review critically analyzes the historical trajectory, current advancements, and future perspectives of vaccine development across AD, PD, and prion diseases. We highlight the evolution from first-generation pan-protein-targeting strategies to precision immunogens focusing on specific pathogenic conformers, the pivotal role of immunomodulation in balancing efficacy and safety, and the emerging landscape of novel vaccine platforms and delivery systems. A central argument advanced herein is the imperative shift from broad-spectrum immune activation to highly targeted, conformation-specific immunotherapies, coupled with early intervention strategies, to unlock the full therapeutic potential of vaccines in preventing and modifying the course of NDs. We propose that integrating lessons from diverse NDs and embracing multi-target, adaptive immunization approaches, alongside advanced biomarker identification, will be critical for achieving clinical success.

Prion diseases are lethal neurodegenerative disorders marked by mitochondrial impairment, oxidative stress, and neuronal apoptosis. Our previous work identified optic atrophy protein 1 (OPA1) as a promising point of intervention, yet the underlying mechanisms are poorly understood. In the present work, we showed that OPA1-mediated protection depends on ATP synthase activity and oligomerization. In N2a cells, PrP106-126 exposure reduced the protein expression levels of OPA1 and key ATP synthase subunits, including the catalytic subunit ATP5A and the oligomerization-associated subunit ATP5k, whereas OPA1 overexpression attenuated this downregulation. Additionally, OPA1 overexpression preserved mitochondrial morphology and cristae structure, alleviated mitochondrial dysfunction, limited oxidative stress, and suppressed mitochondria-dependent apoptotic signaling. Importantly, these protective effects were abolished by pharmacological inhibition of ATP synthase or genetic silencing of ATP5k. Collectively, these results demonstrate that ATP synthase activity and oligomerization are indispensable for OPA1-mediated protection against prion-induced mitochondrial dysfunction, oxidative stress, and neuronal apoptosis, thereby providing novel mechanistic insights and identifying avenues for therapeutic intervention in prion diseases.

Introduction:Mitochondrial dysfunction is an early and critical feature of neuronal injury in prion diseases, a group of fatal transmissible neurodegenerative disorders. Mitochondrial dynamics, a core component of mitochondrial quality control, maintains neuronal homeostasis through balanced fission and fusion. Although mitochondrial fission can be further divided into distinct spatial subtypes, the specific subtype involved in prion-associated neurotoxicity and its regulatory mechanisms remain unclear. This study aimed to identify the mitochondrial fission subtype involved in prion toxicity and elucidate its underlying regulatory mechanisms. Methods:Using live-cell time-lapse imaging, we analyzed mitochondrial fission dynamics in mouse neuroblastoma (N2a) cells treated with the neurotoxic prion peptide PrP106-126. Molecular mechanisms regulating mitochondrial peripheral fission were investigated through protein interaction analysis, mitochondrial-lysosome contact assessment, DRP1 activity analysis, FIS1 knockdown, and pharmacological inhibition using P110. Results:PrP106-126 selectively enhanced mitochondrial peripheral fission, identifying this subtype as a key pathological event underlying early mitochondrial damage. FIS1 acted as a central adaptor regulating this aberrant process by recruiting TBC1D15 to promote RAB7 GTP hydrolysis, thereby destabilizing mitochondria-lysosome contacts. In parallel, FIS1 recruited activated DRP1 to mitochondria. PrP106-126 treatment increased DRP1 Ser616 phosphorylation, decreased DRP1 Ser637 phosphorylation, and enhanced DRP1 GTPase activity, which were required for mitochondrial peripheral fission. FIS1 knockdown and P110-mediated disruption of the DRP1-FIS1 interaction effectively suppressed PrP106-126-induced peripheral mitochondrial fission, restored mitochondrial integrity, and reduced neuronal apoptosis. Discussion:These findings define mitochondrial peripheral fission as a key early pathogenic event in prion toxicity and identify FIS1 as a potential therapeutic target for intervention in prion diseases.

Prion diseases are a group of fatal neurodegenerative disorders characterized by the abnormal folding of cellular prion proteins into pathogenic forms. The development of these diseases is intricately linked to oxidative stress and mitochondrial dysfunction. Irisin, an endogenous myokine, has demonstrated considerable neuroprotective potential due to its antioxidative properties. However, the protective effects of irisin against prion diseases have yet to be clarified. Our findings indicate that treatment with exogenous irisin can mitigate the apoptosis induced by PrP106–126. Additionally, irisin significantly reduces oxidative stress and alleviates the mitochondrial dysfunction triggered by PrP106–126. Furthermore, irisin treatment targets uncoupling protein 2 (UCP2) and activates the AMPK-Nrf2 pathway, substantially improving oxidative stress and mitochondrial dysfunction in N2a cells induced by PrP106–126. These results suggest that irisin represents a novel and promising therapeutic approach for treating prion diseases.

PINK1-Parkin-dependent mitophagy dysfunction is a critical contributor to the accumulation of damaged mitochondria in prion disease, leading to impaired autophagy and neurons apoptosis. However, the specific molecular mechanisms underlying mitophagy dysfunction in prion disease remain unclear. Phosphorylation of Parkin at Ser65 (pSer65-Parkin) is a key determinant for the initiation of PINK1-Parkin-mediated mitophagy. In the prion disease cell model, we observed a significant reduction in pSer65-Parkin and pSer65-Ub expression. PTEN-L, an isoform of the PTEN family, has been implicated in the regulation of PINK1-Parkin-mediated mitophagy. Here, we demonstrate that PTEN-L acts as a phosphatase for Parkin and Ub, exerting a regulatory role in mitophagy in prion disease. We found that PTEN-L expression and mitochondrial translocation were elevated in PrP106-126-treated SH-SY5Y cells. Increased PTEN-L dephosphorylates pSer65-Parkin pSer65-Ub, leading to reduced pSer65-Parkin and pSer65-Ub, then impaired mitophagy initiation. Overexpression of PTEN-L in SH-SY5Y cells mimicked the effects of PrP106-126 treatment, reducing Parkin mitochondrial translocation and pSer65-Parkin levels. PTEN-L knockout alleviates these deficits, restoring Parkin and ubiquitin recruitment to mitochondria and increasing Ser65 phosphorylation in prion disease cell models. Furthermore, PTEN-L deficiency mitigated mitophagy dysfunction and apoptosis in neurons exposed by PrP106-126. These findings suggest that PrP106-126 upregulates PTEN-L, enhancing dephosphorylation of pSer65-Parkin and pSer65-Ub, thereby impairing mitophagy initiation. Targeting PTEN-L expression or activity may represent a novel therapeutic strategy for prion disease.

Mitochondrial dysfunction and oxidative stress are critical factors in the pathogenesis of neurodegenerative diseases. The complex interplay between these factors exacerbates neuronal damage and accelerates disease progression. In neurodegenerative diseases, mitochondrial dysfunction impairs ATP production and promotes the generation of reactive oxygen species (ROS). The accumulation of ROS further damages mitochondrial DNA, proteins, and lipids, creating a vicious cycle of oxidative stress and mitochondrial impairment. This review aims to elucidate the mechanisms by which mitochondrial dysfunction and oxidative stress lead to neurodegeneration, and to highlight potential therapeutic targets to mitigate their harmful effects.

Prion diseases are neurodegenerative diseases that are transmitted between humans and animals, which cause spongiform brain degeneration and neuronal death. Prion diseases are difficult to treat. Mitochondrial damage and oxidative stress occurring early in disease progression. Reducing oxidative stress is a therapeutic strategy for disease. Idebenone (IDE) is an antioxidant that enhances electron transfer in the mitochondrial respiratory chain. To investigate IDE protection mechanisms in prion neuron models, we examined IDE effects on apoptosis, mitochondrial dysfunction, cellular respiratory chain damage, and oxidative stress in N2a cells treated with the prion toxic peptide PrP106-126. IDE effectively alleviated apoptosis and mitochondrial dysfunction, reduced mitochondrial reactive oxygen species (ROS), attenuated lipid peroxidation, improved glutathione percentages, increased important antioxidant enzyme (superoxide dismutase (SOD) and catalase) activities, and elevated mitochondrial DNA levels. IDE also modulated SOD2 deacetylation and oxidative damage by regulating SIRT3. Overall, IDE exerted significant antioxidant effects in our prion disease cell model and may have therapeutic applications for prion disease.

BACKGROUND:Prion diseases (PrDs) are fatal transmissible neurodegenerative disorders caused by misfolded prion protein, which is highly expressed in the brain. Drosophila has been employed as a model system for studying mammalian neurodegenerative diseases. METHODS:Drosophila transgenic for hamster prion protein (HaPrP) was generated by Valium20 transformation. Locomotion, longevity, protease resistance, and histology were assessed, and nontargeted metabolomics analyses were performed to investigate the changes in Drosophila metabolism with the HaPrP expression and metformin treatment. RESULTS:The Drosophila model exhibited pan-neuronal expression of HaPrP, with expression levels increasing with age. Flies displayed reduced climbing ability, shortened lifespan, and vacuolar structures in the brain. Additionally, HaPrP expressed in older flies demonstrated resistance to digestion by 5 μg/mL Proteinase K. The Drosophila model also displayed alterations in protein, lipid, and carbohydrate metabolism. We hypothesize that glutamate, N-acetylaspartate, ceramide, phosphatidylethanolamine, dihydroxyacetone phosphate, ribose-5-phosphate, and pyruvate are key metabolites potentially related to PrDs. Metformin improved locomotor activity, reduced PrPres formation, and ameliorated mitochondrial dysfunction in flies, which may be associated with alterations in succinate, pyruvate, choline, and sphingomyelin levels. CONCLUSIONS:We generated a Drosophila model of PrDs that recapitulates key pathological features observed in mammals. Preliminary applications have demonstrated that the Drosophila model is suitable for PrDs research and the high-throughput screening of potential therapeutic compounds.

Objective To establish a weightlessness simulation animal model using miniature pigs,leveraging the characteristic of multiple systems'tissue structures and functions similar to those of humans,and to observe pathophysiological changes,providing a new method for aerospace research.Methods Nine standard-grade miniature pigs were selected and randomly divided into an experimental group(n=7)and a control group(n=2).The experimental group was fixed using customized metal cages,with canvas slings suspending their hind limbs off the ground,and the body positioned at a-20° angle relative to the ground to simulate unloading for 30 days(24 hours a day).Data on body weight,blood volume,and blood biochemistry indicators were collected at different time points for statistical analysis of basic physiological changes.After the experiment,the miniature pigs were euthanized and tissue samples were collected for histopathological observation of the cardiovascular,skeletal and muscle systems HE and Masson staining.Statistical analysis was also conducted on the thickness of arterial vessels and the diameter of skeletal muscle fibers.Additionally,western blotting was employed to detect the expression levels of skeletal muscle atrophy-related proteins,including muscle-specific RING finger protein 1(MuRf-1)and muscle atrophy F-box(MAFbx,as known as Atrogin-1),while immunohistochemistry was used to detect the expression of glial fibrillary acidic protein(GFAP),an indicator of astrocyte activation in the brain,reflecting the pathophysiological functional changes across systems.Results After hindlimb unloading,the experimental group showed significant decreases in body weight(P＜0.001)and blood volume(P＜0.01).During the experiment,hemoglobin,hematocrit,and red blood cell count levels significantly decreased(P＜0.05)but gradually recovered.The expression levels of alanine aminotransferase and γ-glutamyltransferase initially decreased(P＜0.05)before rebounding,while albumin significantly decreased(P＜0.001)and globulin significantly increased(P＜0.01).Creatinine significantly decreased(P＜0.05).The average diameter of gastrocnemius muscle fibers in the experimental group significantly shortened(P＜0.05),with a leftward shift in the distribution of muscle fiber diameters and an increase in small-diameter muscle fibers.Simultaneously,Atrogin-1 expression in the gastrocnemius and paravertebral muscles significantly increased(P＜0.05).These changes are generally consistent with the effects of weightlessness on humans and animals in space.Furthermore,degenerative changes were observed in some neurons of the cortical parietal lobe,frontal lobe,and hippocampal regions of the experimental group,with a slight reduction in the number of Purkinje cells in the cerebellar region,and a significant enhancement of GFAP-positive signals in the hippocampal area(P＜0.05).Conclusion Miniature pigs subjected to a-20° angle hind limb unloading for 30 days maybe serve as a new animal model for simulating weightlessness,applicable to related aerospace research.

Background:Species of the genus Eimeria cause coccidiosis in chickens,resulting in a huge burden to the poultry industry worldwide.Eimeria tenella is one of the most prevalent chicken coccidia in China,and E.tenella infection causes hemorrhagic cecitis. Methods:Using an established model of coccidiosis in chickens combined with necropsy,imaging of pathological tissue sections,and other techniques,we evaluated the gross and microscopic lesions of cecal tissue within 15days after inoculation with sporulated oocysts and described the endogenetic developmental process and relationship between E.tenella infection and enteritis development in chickens. Results:We observed three generations of merogony and gamogony in E.tenella.We observed gross lesions in the cecum from 84 hpi(hours post inoculation)and microscopic lesions from 60 hpi.The lesions in the cecum mainly exhibited hemorrhagic enteritis.Their severity increased with the onset of the second generation of merogony.The lesions began to alleviate by the end of the endogenous stages of E.tenella. Conclusion:We show,for the first time,the complete observation of a series of changes in enteritis caused by 5 × 103 E.tenella oocysts.This study provides reference materials for E.tenella research and pathological diagnosis.

Mitochondrial damage is an early and key marker of neuronal damage in prion diseases. As a process involved in mitochondrial quality control, mitochondrial biogenesis regulates mitochondrial homeostasis in neurons and promotes neuron health by increasing the number of effective mitochondria in the cytoplasm. Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase that regulates neuronal mitochondrial biogenesis and quality control in neurodegenerative diseases via deacetylation of a variety of substrates. In a cellular model of prion diseases, we found that both SIRT1 protein levels and deacetylase activity decreased, and SIRT1 overexpression and activation significantly ameliorated mitochondrial morphological damage and dysfunction caused by the neurotoxic peptide PrP106–126. Moreover, we found that mitochondrial biogenesis was impaired, and SIRT1 overexpression and activation alleviated PrP106–126-induced impairment of mitochondrial biogenesis in N2a cells. Further studies in PrP106–126-treated N2a cells revealed that SIRT1 regulates mitochondrial biogenesis through the PGC-1α-TFAM pathway. Finally, we showed that resveratrol resolved PrP106–126-induced mitochondrial dysfunction and cell apoptosis by promoting mitochondrial biogenesis through activation of the SIRT1-dependent PGC-1α/TFAM signaling pathway in N2a cells. Taken together, our findings further describe SIRT1 regulation of mitochondrial biogenesis and improve our understanding of mitochondria-related pathogenesis in prion diseases. Our findings support further investigation of SIRT1 as a potential target for therapeutic intervention of prion diseases.

随着航天技术不断发展,航天员太空飞行的时长不断增加.研究发现,航天失重环境可能会使航天员的生理和心理发生一定变化,对航天员的身体健康产生一些影响.为探究这些影响的机制并找出合理的对抗措施,使用实验动物建立模拟失重模型进行深入的研究至关重要,选择与人体组织器官、生理机能和习性相似的实验动物建立模拟失重模型,能更好地帮助相关研究.失重模型应参照能否模拟出由于失重引起心血管骨骼、肌肉等主要系统的变化,来评估模拟失重模型是否成功建立.本文对现有的地面模拟失重动物模型建立和相关研究情况进行了概述,以期为开展相关研究工作提供参考借鉴.

犬猫牙源性肿瘤的发病率逐渐增加.该类肿瘤的发生与牙齿发育密切相关,诊断有一定的难度.通过回顾性病理学方法对2007-2022年收集的犬猫牙源性肿瘤的发病情况进行统计及每类常见牙源性肿瘤的病理学表现进行分析,为牙源性肿瘤的病理学诊断提供可靠依据,并对临床治疗及预后的判断提供有意义的指导.中国农业大学动物医学院国家动物海绵状脑病实验室收集来自全国多家宠物医院的犬猫口腔肿瘤组织样品或切片371例,对病例信息进行统计.对典型病例进行 HE染色以观察其特征性病理学表现,辅助以CK14及vimentin免疫组织化学染色分别对牙源性上皮成分与牙源性外间质成分进行鉴别.结果显示:在371例犬猫口腔肿瘤组织样品或切片中,有117例为牙源性肿瘤,其中犬93例,猫24例.在犬中,外周牙源性纤维瘤的发病率最高,雄性发病率高于雌性,其他常见肿瘤包括犬棘细胞型成釉细胞瘤,牙龈增生,成釉细胞瘤,成釉细胞纤维瘤与纤维牙瘤以及混合型牙瘤.在猫中,牙龈增生最常见,没有性别倾向,其他常见肿瘤包括外周牙源性纤维瘤与成釉细胞瘤.牙源性肿瘤在犬猫中有较高发病率,该类肿瘤的精准诊断值得更多的关注.对牙源性肿瘤的诊断来说,确定牙源性上皮的存在至关重要,CK14可以作为牙源性上皮良好的标志物,为准确的组织病理学诊断提供辅助,并对临床治疗及预后的判断提供有意义的指导.

Proper mitochondrial performance is imperative for the maintenance of normal neuronal function to prevent the development of neurodegenerative diseases. Persistent accumulation of damaged mitochondria plays a role in prion disease pathogenesis, which involves a chain of events that culminate in the generation of reactive oxygen species and neuronal death. Our previous studies have demonstrated that PINK1/Parkin-mediated mitophagy induced by PrP106-126 is defective and leads to an accumulation of damaged mitochondria after PrP106-126 treatment. Externalized cardiolipin (CL), a mitochondria-specific phospholipid, has been reported to play a role in mitophagy by directly interacting with LC3II at the outer mitochondrial membrane. The involvement of CL externalization in PrP106-126-induced mitophagy and its significance in other physiological processes of N2a cells treated with PrP106-126 remain unknown. We demonstrate that the PrP106-126 peptide caused a temporal course of mitophagy in N2a cells, which gradually increased and subsequently decreased. A similar trend in CL externalization to the mitochondrial surface was seen, resulting in a gradual decrease in CL content at the cellular level. Inhibition of CL externalization by knockdown of CL synthase, responsible for de novo synthesis of CL, or phospholipid scramblase-3 and NDPK-D, responsible for CL translocation to the mitochondrial surface, significantly decreased PrP106-126-induced mitophagy in N2a cells. Meanwhile, the inhibition of CL redistribution significantly decreased PINK1 and DRP1 recruitment in PrP106-126 treatment but had no significant decrease in Parkin recruitment. Furthermore, the inhibition of CL externalization resulted in impaired oxidative phosphorylation and severe oxidative stress, which led to mitochondrial dysfunction. Our results indicate that CL externalization induced by PrP106-126 on N2a cells plays a positive role in the initiation of mitophagy, leading to the stabilization of mitochondrial function.

Mitochondria play key roles in bioenergetics, metabolism, and signaling; therefore, stable mitochondrial function is essential for cell survival, particularly in energy-intensive neuronal cells. In neurodegenerative diseases, damaged mitochondria accumulate in neurons causing associated bioenergetics deficiency, impaired cell signaling, defective cytoplasmic calcium buffering, and other pathological changes. Mitochondrial quality control is an important mechanism to ensure the maintenance of mitochondrial health, homeostasis, and mitophagy, the latter of which is a pathway that delivers defective mitochondria to the lysosome for degradation. Defective mitophagy is thought to be responsible for the accumulation of damaged mitochondria, which leads to cellular dysfunction and/or death in neurodegenerative diseases. PINK1/Parkin mainly regulates ubiquitin-dependent mitophagy, which is crucial for many aspects of mitochondrial physiology, particularly the initiation of autophagic mechanisms. Therefore, in the present review, we summarize the current knowledge of the conventional mitophagy pathway, focusing on the molecular mechanisms underlying mitophagy dysregulation in prion disease and other age-related neurodegenerative diseases, especially in relation to the PINK1/Parkin pathway. Moreover, we list the inducers of mitophagy that possess neuroprotective effects, in addition to their mechanisms related to the PINK1/Parkin pathway. These mechanisms may provide potential interventions centered on the regulation of mitophagy and offer therapeutic strategies for the treatment of neurodegenerative diseases.

目的 探讨海立啮齿杆菌(Rh)外膜蛋白A(OmpA)原核表达蛋白对小鼠的免疫效果.方法 采用原核表达、镍离子亲和层析纯化,制备Rh OmpA重组蛋白,并用SDS-PAGE和Western blot进行鉴定.获得的OmpA目的蛋白经腹腔、肌肉联合注射和滴鼻两种方案免疫ICR小鼠,由ELISA方法测定其抗体滴度.再分别将Rh ATCC12555、嗜肺啮齿杆菌(Rp)ATCC35149和Rh分离株PP320对免疫小鼠腹腔接种攻毒,评价重组蛋白OmpA对小鼠的保护效果.结果 以表达蛋白OmpA为包被抗原的ELISA方法检测免疫小鼠血清中OmpA特异性抗体水平,平均抗体滴度为19.84log2.免疫小鼠对两标准菌株和PP320的保护率分别为60％、60％和80％,与未免疫小鼠相比死亡率显著降低(P<0.001).基于OmpA表达蛋白建立的ELISA方法检测嗜肺巴斯德杆菌(Pp)阳性小鼠血清,抗体阳性率为60％.结论 制备的Rh OmpA表达蛋白有良好的免疫原性,对Rh和Rp具有一定的保护效果,为实验动物中呼吸道病原菌的防控提供参考.

丁酸钠是丁酸加工成钠盐形式,丁酸钠具有抗感染、提高机体免疫力、稳定肠道菌群等功效,文中结合近年来国内外的研究进展,重点总结了丁酸钠诱导机体细胞凋亡的具体机制,包括丁酸钠激活死亡受体通路、线粒体通路和内质网应激通路等.并探讨了丁酸钠改善疾病动物模型的具体机制.希望为丁酸钠在疾病预防和治疗中提供新的思路.

Prion disease represents a group of fatal neurogenerative diseases in humans and animals that are associated with energy loss, axonal degeneration, and mitochondrial dysfunction. Axonal degeneration is an early hallmark of neurodegeneration and is triggered by SARM1. We found that depletion or dysfunctional mutation of SARM1 protected against NAD(+) loss, axonal degeneration, and mitochondrial functional disorder induced by the neurotoxic peptide PrP106-126. NAD(+) supplementation rescued prion-triggered axonal degeneration and mitochondrial dysfunction and SARM1 overexpression suppressed this protective effect. NAD(+) supplementation in PrP106-126-incubated N2a cells, SARM1 depletion, and SARM1 dysfunctional mutation each blocked neuronal apoptosis and increased cell survival. Our results indicate that the axonal degeneration and mitochondrial dysfunction triggered by PrP106-126 are partially dependent on SARM1 NADase activity. This pathway has potential as a therapeutic target in the early stages of prion disease.

Failed communication between mitochondria and lysosomes causes dysfunctional mitochondria, which may induce mitochondria-related neurodegenerative diseases. Here, we show that RAB7A, a small GTPase of the Rab family, mediates the crosstalk between these two important organelles to maintain homeostasis in N2a cells treated with PrP106–126. Specifically, we demonstrate that mitophagy deficiency in N2a cells caused by PrP106–126 is associated with dysregulated RAB7A localization in mitochondria. Cells lacking RAB7A display decreased mitochondrial colocalization with lysosomes and significantly increased mitochondrial protein expression, resulting in inhibited mitophagy. In contrast, overexpression of GTP-bound RAB7A directly induces lysosome colocalization with mitochondria. Further study revealed that GTP-bound RAB7A protects mitochondrial homeostasis by supporting autophagosome biogenesis. Moreover, we suggest that depletion of RAB7A leads to gross morphological changes in lysosomes, which prevents autophagosome–lysosome fusion and interferes with the breakdown of autophagic cargo within lysosomes. Overexpression of GTP-bound RAB7A can also alleviate PrP106–126-induced morphological damage and dysfunction of mitochondria, reducing neuronal apoptosis. Collectively, our data demonstrate that RAB7A successfully drives mitochondria to the autophagosomal lumen for degradation, suggesting that the communication of proteotoxic stress from mitochondria to lysosomes requires RAB7A, as a signaling molecule, to establish a link between the disturbed mitochondrial network and its remodeling. These findings indicate that small molecules regulating mitophagy have the potential to modulate cellular homeostasis and the clinical course of neurodegenerative diseases. Proposed model of mitophagy regulated by RAB7A. (1) Accumulating PrP106–126 induced mitophagy. (2) RAB7A is recruited to mitochondria. (3) ATG5-12 and ATG9A (5) vesicles are recruited to the autophagosome formation sites in a RAB7A-dependent manner. The ATG5-12 complex recruits and anchors LC3-I to form active LC3-II (4), accelerating mitophagosomal formation. The ATG9A vesicles are thought to be a source of membranes for autophagosome assembly. The recruitment of proteins and lipids induces membrane expansion and subsequent closure to form the mitophagosome. (6) Maintenance of the normal low lysosomal PH depends on active (GTP-bound) RAB7A. (7) RAB7A recruits effector molecules responsible for tight membrane interactions, and directly or indirectly, the subsequent autophagosome merges with the lysosome, and the cargo is completely degraded.