bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2026–07–19
thirteen papers selected by
Irene Sambri, TIGEM
  1. N-acetyl-L-leucine normalizes Transcription Factor EB activity by stereospecific bidirectional modulation in a HeLa cell model of Niemann-Pick disease type C.
  2. YAP1 depletion enhances TAZ and its complexation with TEAD4 and AP-1 heterodimer C-JUN/FOSB in gastric cancer progression and metastasis.
  3. Rag GTPases and mTORC1 regulate intestinal stem cell activity in response to nutrient availability.
  4. Spalt-related is an inhibitor of mTORC1-mediated growth activated by the integrated stress response.
  5. Orchestration of Autophagy and Senescence: Kinases Take the Center Stage.
  6. GATOR2 regulates the nutrient-dependent recruitment of GATOR1 to lysosomes.
  7. Metabolite glues as a means of purine sensing and chemotherapeutic response.
  8. Lysosomes and lysosomal dysfunction in ageing biology.
  9. YAP/TAZ Signaling in Endothelial Cells Mediates the Pathogenesis of Abdominal Aortic Aneurysm Formation.
  10. Schizophrenia and bipolar disorder risk gene AKAP11 sustains cognitive function by regulating TFEB-mediated autophagy.
  11. Cardiac Metabolism in Healthy, Senescent and Diseased States.
  12. The Emerging Role of mTOR in Shaping the Cancer Cell Secretome and Plasticity.
  13. Rewiring Lipid Metabolism: PINK1 as a Central Regulator of Mitochondrial Homeostasis in Parkinson's Disease.
  1. PLoS One. 2026 ;21(7): e0353834
    N-acetyl-L-leucine normalizes Transcription Factor EB activity by stereospecific bidirectional modulation in a HeLa cell model of Niemann-Pick disease type C.
    Lianne C Davis, Wim Annaert, Rebecca Braine, Grant C Churchill, Mallory Factor, Taylor Fields, Marc Patterson, Frances Platt, Dawn Shepherd, Michael Strupp, Antony Galione.
      Levacetylleucine (Aqneursa™), an acetylated derivative and pro-drug of L-leucine, is the only FDA-approved monotherapy for Niemann-Pick disease type C (NPC). Its acetyl group enables transport via monocarboxylate transporters, supporting blood-brain barrier penetration and efficient cellular uptake. Inside cells, levacetylleucine is metabolised by acylases, generating elevated levels of L-leucine that enhance mitochondrial bioenergetics and is thought to ameliorate lysosomal dysfunction indirectly. Here, we describe a direct effect of levacetylleucine on lysosomal regulation through modulation of TFEB, the master transcription factor for lysosomal and autophagy genes. Levacetylleucine rapidly alters TFEB translocation between the cytoplasm and the nucleus in a biphasic, homeostasis-restoring manner. In wild-type HeLa cells, levacetylleucine promotes TFEB activation and nuclear localisation. However, in NPC1 disease models, where we show that TFEB is over-activated and enriched in the nucleus due to lysosomal stress, levacetylleucine reduces nuclear TFEB and restores a more normal cytoplasmic-to-nuclear balance. These effects occur at clinically relevant concentrations associated with lysosomal storage reduction. The effects of the drug are stereospecific: while the L-enantiomer is active, the D-enantiomer and racemate show no effect, revealing the antagonistic properties of the D-enantiomer. This bidirectional normalisation of TFEB activity highlights a direct mechanism through which levacetylleucine modulates lysosomal and autophagic pathways in the HeLa cell model, giving mechanistic insight into its therapeutic potential in NPC, and also across diverse neurological and neurodevelopmental disorders.
    DOI:  https://doi.org/10.1371/journal.pone.0353834
  2. Cancer Heterog Plast. 2026 ;pii: 0003. [Epub ahead of print]3(1):
    YAP1 depletion enhances TAZ and its complexation with TEAD4 and AP-1 heterodimer C-JUN/FOSB in gastric cancer progression and metastasis.
    Jingjing Wu, Dipti Athavale, Curt Balch, Junsong Zhao, Gengyi Zou, Yibo Fan, Yanting Zhang, Joseph Zhao, Mikel Ghelfi, Anthony Pompetti, Gennaro Calendo, Ailing Scott, Shan Shao, Xiaodan Yao, Melissa Pool Pizzi, Christopher Vellano, Vladimir Khazak, Sheng Zhang, Timothy A Yap, Shilpa S Dhar, Raghav Sundar, Francis Spitz, Generosa Grana, Jaffer A Ajani, Shumei Song.
       Background: Dysregulation of the Hippo signaling pathway, characterized by aberrant activation of the transcriptional coactivators YAP1 and TAZ, drives tumor progression, immunosuppression, and metastasis. Hippo pathway components are emerging therapeutic targets in several solid tumors, however, the expression profiles of Hippo coactivators YAP1, TAZ, and their transcriptional factors TEAD1-4 in gastric cancer peritoneal metastases (GCPMs), and their therapeutic value, are unknown. In this study, we sought to determine the expression status of YAP1, TAZ, and TEAD1-4 in GCPMs and to evaluate whether dual targeting of YAP1 and TAZ provides superior antitumor activity compared with inhibition of either coactivator alone.
    Methods: Expression of YAP1, TAZ, and TEAD1-4 was examined in GCPMs by single-cell RNA sequencing and co-immunofluorescent staining. Functional studies using genetic knockout and antisense oligonucleotide (ASO) inhibition of YAP1 or TAZ were performed to assess antineoplastic effects in vitro and in vivo. Co-immunoprecipitation and luciferase reporter assays were used to characterize YAP1/TAZ interactions with TEADs and AP-1 components (JUN and FOSB) and to quantify transcriptional activity. Antitumor efficacy was validated in patient-derived xenograft (PDX) and KP-Luc2 syngeneic models.
    Results: YAP1, TAZ, and TEADs1- 4 were highly coexpressed in GCPMs and correlated with poor survival. YAP1 inhibition alone elicited compensatory upregulation of TAZ, while combined inhibition of both coactivators maximally repressed cell proliferation and invasion in vitro, and tumor growth in vivo. Increased TAZ complexation with TEAD4 and AP-1 (c-JUN and FOSB) heterodimer was observed following YAP1 knockdown or pharmacological ASO inhibition. Dual inhibition of YAP1 and TAZ was required to maximally suppress YAP1/TAZ expression and reduce their nuclear accumulation, transactivation of TEAD, and activation of downstream genes.
    Conclusions: These findings show that combined YAP1 and TAZ inhibition holds promise for the treatment of GCPM, a highly lethal disease with an urgent need for novel treatment options.
    Keywords:  Antisense oligonucleotide (ASO); Hippo pathway; TAZ; TEAD1-TEAD4; YAP1; gastric cancer peritoneal metastasis (GCPM); targeted therapy
    DOI:  https://doi.org/10.47248/chp2603010003
  3. J Cell Biol. 2026 Sep 07. pii: e202510172. [Epub ahead of print]225(9):
    Rag GTPases and mTORC1 regulate intestinal stem cell activity in response to nutrient availability.
    Weikang Fan, Churui Ge, Chunmei Niu, Shuang Liu, Peng Wang, Heng Li, Yang Cheng, Yingying Lu, Youheng Wei.
      The intestinal epithelium, predominantly composed of enterocytes (ECs), integrates dietary cues to regulate intestinal stem cell (ISC) activity and maintain intestinal homeostasis. However, the underlying mechanisms remain incompletely understood. Here, we demonstrate the functions of essential nutrient-sensing mediators Rag GTPases and mTORC1 on Drosophila ISC activity. Inhibition of Rag GTPases in ECs triggers Mitf activation, which subsequently induces Upd3 expression to non-cell autonomously increase the ISC proliferation and differentiation through stimulating the JAK-STAT pathway. Inactivation of mTORC1 in ECs also activates the Upd3-JAK-STAT axis and increases ISC activity, but through a Mitf-independent mechanism. Moreover, in contrast to mTORC1 inactivation blocking ISC proliferation and differentiation, depletion of Rag GTPases in ISCs shows no obvious cell autonomous effect on ISC activity. Consistent with inhibition of the nutrient-responsive pathway in ECs promoting ISC proliferation, long-term nutrient starvation enhances ISC activity and Upd3 expression. Together, our findings reveal a nutrient-sensing regulatory network that controls ISC proliferation involving the Rag GTPases-Mitf axis and mTORC1 activity.
    DOI:  https://doi.org/10.1083/jcb.202510172
  4. EMBO J. 2026 Jul 11.
    Spalt-related is an inhibitor of mTORC1-mediated growth activated by the integrated stress response.
    Onur Deniz, Ying Liu, Tuuli Kirkinen, Krista Kokki, Kateryna Gaertner, Pau Clavell-Revelles, Jaakko Mattila, Ville Hietakangas.
      Anabolic and catabolic processes are coordinated by a conserved regulatory network, which includes the nutrient-sensing protein kinase mTOR complex 1 (mTORC1) and the insulin- and stress-responsive transcription factor FoxO. In a physiological setting, these regulators align growth, storage, reproduction, and aging with nutrient availability. Here, we identify transcription factor Spalt-related (Salr), previously implicated in organogenesis, as a negative regulator of growth and lipid storage in Drosophila melanogaster. Salr activates catabolic gene expression and restricts mTORC1-mediated cell growth in the Drosophila fat body. The genomic binding of Salr overlaps extensively with that of FoxO, and a similar convergence is observed for their mammalian homologs, SALL1 and FOXO1. Both Salr and FoxO are activated upon fasting, but respond to distinct cues: while FoxO displays transient activation and is responsive to AKT inhibition, Salr is activated in a slow and sustained manner through the integrated stress response. Once activated, Salr counters nuclear localization of FoxO. Taken together, we show that Salr and FoxO are growth-inhibitory transcription factors that act in a convergent manner to respond to nutrient stress through distinct cues.
    DOI:  https://doi.org/10.1038/s44318-026-00858-1
  5. Cells. 2026 Jun 28. pii: 1176. [Epub ahead of print]15(13):
    Orchestration of Autophagy and Senescence: Kinases Take the Center Stage.
    Alakananda Basu.
      Autophagy was originally identified as a survival mechanism to allow cells to survive under nutrient-deprived or stressful conditions whereas cellular senescence was considered a tumor-suppressive mechanism. Both processes can be induced by similar stimuli and can influence each other. There have been continued debates about whether they are causally linked, whether autophagy promotes or prevents senescence or if they are independent of each other. Protein kinases play integral roles in cell fate decision and have a major influence on both autophagy and senescence. While mechanistic target of rapamycin complex 1 is considered the master regulator of autophagy, it also influences senescence. Mitogen-activated protein kinases originally associated with senescence can regulate autophagy. While there have been numerous review articles on the interplay between autophagy and senescence, a comprehensive review on how various kinases participate in this interplay is lacking. The purpose of this review is to learn lessons from some old and recent studies to understand how kinases contribute to this changing field. Since both autophagy and senescence can have beneficial and detrimental effects and kinases are important drug targets, insights regarding how kinases orchestrate these two processes should help develop therapeutic strategies to treat diseases, such as aging and cancer.
    Keywords:  AMPK; CDK; JNK; PI3K/Akt/mTOR; Ras/Raf/MEK/ERK; ULK; aging; cancer; p38 MAPK
    DOI:  https://doi.org/10.3390/cells15131176
  6. bioRxiv. 2026 Jul 08. pii: 2026.07.07.737070. [Epub ahead of print]
    GATOR2 regulates the nutrient-dependent recruitment of GATOR1 to lysosomes.
    Yingbiao Zhang, Chun-Yuan Ting, Shu Yang, Richard Garcia, Mary Lilly.
      TORC1 is a central regulator of cellular metabolism. TORC1 activation depends on its recruitment to the lysosome, a process mediated by the Rag GTPases and their upstream regulator, the GATOR complex. GATOR consists of two subcomplexes: GATOR1, which converts the Rag GTPases into an inactive form during nutrient starvation by acting as a GAP towards RagA, and GATOR2, which counteracts GATOR1 through an unknown mechanism. Here we dissect the GATOR-Rag GTPases network at the cellular and subcellular level in Drosophila using genomically tagged proteins. We find that GATOR2 maintains GATOR1 in the GAP-inactive state under nutrient-replete conditions. Moreover, using fluorescent recovery after photobleaching we show that while GATOR1 and GATOR2 are recruited to lysosomes as a supercomplex in fed conditions, their recruitment becomes decoupled during starvation. Taken together, our findings support a model in which GATOR1 forms an inactive supercomplex with GATOR2 under nutrient-rich conditions. However, upon nutrient starvation, this supercomplex dissociates, enabling GATOR1 to adopt a GAP-active state and inhibit the Rag GTPases, thereby preventing the recruitment and activation of TORC1 on lysosomes. Finally, our data identify Wdr59 as a critical regulator of this nutrient-dependent remodeling that is required to relieve GATOR2-mediated inhibition of GATOR1.
    DOI:  https://doi.org/10.64898/2026.07.07.737070
  7. Nature. 2026 Jul 15.
    Metabolite glues as a means of purine sensing and chemotherapeutic response.
    Samuel R Witus, Megan M Kober, Heegwang Roh, Zhi Yang, Fouad Choueiry, Avani S Ghate, Denis V Titov, Michael Rapé.
      Molecular glues stabilize weak interactions to impart new functionalities to complexes1-3. Although molecular glues have been described in plant signalling and as human therapeutics4,5, it is unclear whether this modality provides endogenous regulation in human cells. Here we show that purine nucleotides are molecular glues that tether the rate-limiting enzyme in purine biosynthesis-phosphoribosyl pyrophosphate amidotransferase (PPAT)-to its inhibitor NUDT5. This mechanism allows cells to sense the levels of purines and to establish essential feedback control of their synthesis. We refer to such molecules as metabolite glues. Thiopurine chemotherapeutics6, which have been in clinical use since the 1950s, glue the same complex but adopt distinct orientations for enhanced function. Unlike most known glues, the PPAT-NUDT5 metabolite-glue pocket can adjust its conformation to notable compound alterations, enabling increased glue potency and improved on-target activity. We therefore identify endogenous metabolite glues as a mode of nutrient sensing that can be exploited for therapeutic benefit.
    DOI:  https://doi.org/10.1038/s41586-026-10790-3
  8. Nat Cell Biol. 2026 Jul 15.
    Lysosomes and lysosomal dysfunction in ageing biology.
    Matthew L Steinhauser, Yuan Liu, Stacey J Sukoff Rizzo, Bill B Chen, Toren Finkel, Jay Xiaojun Tan.
      Lysosomes are essential regulators of cellular homeostasis. Emerging evidence positions lysosomes as both vulnerable targets and active drivers of ageing biology. During ageing, lysosomes exhibit impaired biogenesis, defective acidification, reduced hydrolytic activity and compromised membrane integrity. These defects impair the clearance of damaged organelles and macromolecules and promote cellular stress responses, inflammageing and senescence, causing age-dependent functional decline across tissues. Lysosomal dysfunction has been increasingly linked to age-related diseases, including neurodegeneration, cardiometabolic disorders and increased susceptibility to infection, among others. Thus, lysosomal dysfunction is a hallmark of ageing that drives age-related pathology. Here we review recent progress in lysosomal biogenesis and quality control, discuss how lysosomes intersect with fundamental ageing mechanisms and evaluate emerging therapeutic strategies that target lysosomes to promote healthy ageing and potentially ameliorate age-associated pathologies.
    DOI:  https://doi.org/10.1038/s41556-026-02007-6
  9. bioRxiv. 2026 Jul 07. pii: 2026.07.01.735919. [Epub ahead of print]
    YAP/TAZ Signaling in Endothelial Cells Mediates the Pathogenesis of Abdominal Aortic Aneurysm Formation.
    Walker R Ueland, Paolo Bellotti, Jeff A Valisno, Aravinthan Adithan, Denny J M Kollareth, Jonathan R Krebs, Michael J Fassler, Gang Su, Shiven Sharma, Xuanxuan Yu, Guoshaui Cai, Ashish K Sharma, Gilbert R Upchurch.
       Background: Abdominal aortic aneurysms (AAA) are characterized by dilation of the aorta that can lead to aortic rupture and death. The transcriptional co-activators Yes-Associated Protein (YAP) and WW-domain-containing transcriptional co-activator with PDZ-binding motif (TAZ) are mechanosensitive effectors of the highly conserved Hippo signaling pathway. It is hypothesized that cell-specific YAP/TAZ signaling in endothelial cells (EC) plays a pivotal role in mediating AAA formation and rupture.
    Methods: Single-cell RNA-sequencing in human AAAs was performed and differentially expressed genes (DEGs) were identified in the endothelial cell cluster. YAP/TAZ mRNA and protein expression were also assessed in human AAA and control aortic tissue. Two established murine AAA models were used with male C57BL/6 and EC-CreER T 2 -YAP fl/fl /TAZ fl/fl mice with/without Verteporfin (VPF, YAP/TAZ inhibitor) and XMU-MP-1 (YAP/TAZ activator) treatments. On postoperative days 14 and 28, aortic diameter, histology, cytokine, and MMP2 expressions were evaluated.
    Results: A significant alteration in EC-specific differentially expressed YAP/TAZ-related genes was observed in which 242 genes were upregulated and 71 genes were downregulated in AAA compared to controls. Human AAA tissue showed a significant increase in YAP and TAZ protein expressions compared to controls. Elastase-treated EC-YAP/TAZ -/- mice showed a significant decrease in AAA diameter compared to littermate controls. Histological quantification revealed preservation of α-smooth muscle actin, reduced elastin fiber breaks, and decreased macrophage infiltration in EC-YAP/TAZ -/- mice compared to littermate controls. Importantly, pharmacological inhibition of YAP/TAZ using VPF significantly attenuated AAAs in two experimental murine models. In vitro data demonstrates that VPF inhibits endothelial cell YAP expression, downregulating pathways associated with pathogenic angiogenesis and vascular inflammation.
    Conclusions: These data suggest that EC-specific YAP/TAZ signaling mediates AAA formation. Pharmacological inhibition of the Hippo pathway can significantly mitigate aortic inflammation and vascular remodeling to decrease the progression of AAAs and prevent aortic rupture.
    Highlights: Expression of YAP/TAZ in endothelial cells is dysregulated in human AAAs. Experimental murine models demonstrate that: a) endothelial-cell specific deletion of YAP/TAZ protects against AAA formation, and pharmacologic alteration with b) verteporfin attenuates AAA formation, and c) XMU-MP-1 significantly exacerbates aortic inflammation, vascular remodeling, and rupture. Verteporfin inhibits endothelial YAP/TAZ activation by modulating ECM remodeling, pathogenic angiogenesis, pro-inflammatory cytokine and chemokine expression.
    DOI:  https://doi.org/10.64898/2026.07.01.735919
  10. Cell Death Differ. 2026 Jul 16.
    Schizophrenia and bipolar disorder risk gene AKAP11 sustains cognitive function by regulating TFEB-mediated autophagy.
    Zhiqiang Deng, Yuxuan Kan, Jia Liu, Ka Yee Ying, Yuxiao Yang, Xinjie Guan, Xiaogang Xu, Chengfu Su, Jing Lu, Kejia Lu, Yinchi Chen, Senthilkumar Krishnamoorthi, Jia-Hong Lu, Ashok Iyaswamy, King-Ho Cheung, Ju-Xian Song, Zhenyu Yue, Min Li.
      Schizophrenia (SCZ) and bipolar disorder (BD) share cognitive impairments and autophagy disruptions, with haploinsufficiency of AKAP11 (A-kinase anchoring protein 11) emerging as a major genetic risk factor for both disorders, though its functional role remains poorly understood. Here, we demonstrate that acute Akap11 depletion in the mouse hippocampus induces cognitive deficits, accompanied by synaptic dysfunction and autophagy dysregulation, implicating Akap11 deficiency in cognitive impairments via disrupted autophagic processes. Using in vitro models, we show that AKAP11 regulates autophagy initiation and lysosomal activity in various cell types, including neuronal cells. Mechanistically, AKAP11 deficiency results in increased phosphorylation of transcription factor EB (TFEB), impairing its nuclear translocation and downregulating its target genes critical for autophagy and lysosome biogenesis. Further, we identify an interaction between AKAP11 and PPP3CB, a phosphatase responsible for TFEB dephosphorylation, and demonstrate that inhibition of PPP3CB abrogates AKAP11-mediated TFEB dephosphorylation. Importantly, in vivo administration of a TFEB activator reduces the accumulation of autophagy substrates and mitigates cognitive impairments in Akap11-deficient mice, highlighting TFEB activation as a potential therapeutic strategy. Collectively, our findings establish AKAP11 as a key regulator of the autophagy-lysosome pathway and cognitive function, providing novel insights into the pathophysiology of SCZ and BD and suggesting therapeutic potential in targeting TFEB-mediated autophagy.
    DOI:  https://doi.org/10.1038/s41418-026-01813-7
  11. Cells. 2026 Jun 26. pii: 1164. [Epub ahead of print]15(13):
    Cardiac Metabolism in Healthy, Senescent and Diseased States.
    Uma Bapat, Shahem Albean, Lei Hao, Eun Jung Lee.
      Cardiovascular disease (CVD) is the leading cause of mortality worldwide. The healthy adult heart depends on flexible energy use, but a diseased or injured heart is associated with a loss of flexibility and metabolic remodeling. Since metabolism plays a central role in cardiac health and disease, there is a growing need to understand how metabolic reprogramming contributes to cardiac dysfunction and impaired CM maturation. Human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) are widely used as a platform to study human cardiac development and disease mechanisms. However, current models are limited by metabolic and structural immaturity. This review provides an overview of the dynamic shifts in cardiac metabolic states from fetal development to senescence, while delineating the metabolic signatures of healthy versus disease states. These metabolic switches are orchestrated by a complex interplay of upstream signals driven by variations in substrate availability, post-translational modifications and key transcriptional regulatory networks, which ultimately regulate downstream cardiac remodeling and pathological cascades. As cardiac metabolic function is affected by a coordinated multicellular network, this review also includes the metabolic crosstalk between CMs and non-CMs, including fibroblasts, endothelial cells and immune cells. In addition, various strategies to further mature hiPSC-CMs are summarized to enhance their metabolic profiles. Investigating cardiac metabolic shifts bridges developmental biology, stem cell biology, and regenerative cardiology by revealing how energy metabolism governs cellular identity, maturation, and regenerative potential. These insights are essential for improving stem-cell-derived CMs for disease modeling, drug discovery, and heart repair.
    Keywords:  cardiac metabolism; human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs); metabolic maturation; metabolic remodeling; senescence
    DOI:  https://doi.org/10.3390/cells15131164
  12. Mol Cell Biol. 2026 Jul 14. 1-22
    The Emerging Role of mTOR in Shaping the Cancer Cell Secretome and Plasticity.
    Tyler T Cooper, Ivan Topisirovic, Lynne M Postovit.
      As tumors expand and encounter hypoxia and nutrient deprivation, cancer cells must establish tight coordination between metabolic reprogramming, protein synthesis and secretory activity to enable effective adaptation. The mechanistic target of rapamycin (mTOR) pathway plays a major role in coordinating protein synthesis and energy metabolism. Dysregulation of mTOR signaling is a hallmark of neoplasia and it contributes to tumorigenesis, metastasis, and therapeutic resistance. In this review, we discuss the emerging role of mTOR in shaping the cancer secretome and examine the implications of mTOR-dependent secretory regulation within the tumor microenvironment. Specifically, we highlight how alterations in secretory output downstream of mTOR influence extracellular matrix remodeling, angiogenesis, immune evasion, and the development of chemoresistance. This review integrates current evidence to provide a comprehensive perspective on the intersection between mTOR signaling, metabolism, protein synthesis and secretory remodeling in cancer. Specifically, we emphasize emerging links between aberrant mTOR function in cancer and secretory programs in the context of cancer cell plasticity and therapeutic resistance.
    Keywords:  cancer; chemoresistance; extracellular vesicles; mTOR; metabolism; microenvironment; plasticity; protein synthesis; secretion; stress-response
    DOI:  https://doi.org/10.1080/10985549.2026.2699146
  13. Int J Mol Sci. 2026 Jul 07. pii: 6073. [Epub ahead of print]27(13):
    Rewiring Lipid Metabolism: PINK1 as a Central Regulator of Mitochondrial Homeostasis in Parkinson's Disease.
    Ana Beatriz Ramos, Vanessa Alexandra Morais.
      Increasing evidence highlights a tight interplay between lipid metabolism and mitochondrial homeostasis in neurons, with disruptions in either pathway amplifying cellular vulnerability. PTEN-induced kinase 1 (PINK1), a familial Parkinson's disease (PD)-related gene and a key regulator of mitochondrial quality control and homeostasis, emerges at the intersections of lipid metabolic pathways, influencing membrane composition, fatty acid utilization, and neuronal energy balance. Within this review, we discuss the role of mitochondria as hubs for lipid metabolism, the mechanisms and functional consequences of neuronal lipid handling, and the complex bidirectional relationship between lipid dysregulation and PD pathology. Special focus is given to lipid-mitochondria crosstalk and how PINK1 orchestrates this interface to maintain neuronal homeostasis. Finally, we consider therapeutic perspectives that target lipid and mitochondrial pathways, highlighting strategies to restore cellular function and PD pathology.
    Keywords:  PINK1; Parkinson’s disease; lipids; metabolism; mitochondria
    DOI:  https://doi.org/10.3390/ijms27136073
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