The data were retrieved from the Web of Science Core Collection (WoSCC) and Scopus from 2004 until the date of the search on 11 June 2025. Both databases were utilized to ensure comprehensive coverage and minimize the risk of missing relevant publications. WoSCC is a leading academic database recognized for its comprehensive coverage of scientific and authoritative publications, reliable citation indexing, and detailed citation information, including keywords and references, making it the most frequently used source in bibliometric studies (14, 15). Scopus complements WoSCC by indexing a broader range of journals, offering extensive coverage in the social sciences and life sciences, and providing robust author and affiliation level metrics that facilitate cross-disciplinary citation analyses and trend detection (14).

The study search used a combination of Medical Subject Headings (MeSH) terms and related entry terms sourced from PubMed. The keywords “mitophagy” and “neurodegenerative diseases” were employed with Boolean logic, with the complete search strategy, including all search terms and Boolean operators, as well as a flowchart illustrating the literature search, screening, and deduplication process, provided in the Supplementary file for transparency. This approach ensured that the search captured relevant articles discussing mitophagy in relation to ND. To refine the search results, built-in filters within the Web of Science and Scopus were applied to restrict the time span, document types, and languages. Only articles and reviews published in English were included in the final dataset. This filtering approach ensured the inclusion of high-quality and relevant publications, while maintaining focus on the most impactful research in the field.

The collected data were first processed in R to identify and remove duplicate records, ensuring accuracy and uniqueness in the dataset. The processed data were analyzed using Bibliometrix and Excel for descriptive statistics, while VOSviewer, CiteSpace and and Scimago Graphica for the visualization of bibliometric networks. VOSviewer was primarily employed to construct and analyze co-authorship and co-citation networks. CiteSpace was also used for co-authorship and co-citation network analysis, as well as for generating theme clusters, cluster timelines, and detecting keyword bursts. Scimago Graphica was utilized specifically to generate international collaboration maps. These tools facilitated the identification of major research trends, contributing countries, influential institutions, key researchers, seminal publications, and significant keywords and themes in the field of mitophagy and ND.

In the analyses conducted, different tools were employed to extract and process the data. The Bibliometrix R package (4.4.1) (16) were utilized to gather information on countries/regions, journals, and authors. For bibliometric analyses, including the examination of co-citation and co-occurrence networks, software tools VosViewer (1.6.19) (17), CiteSpace (6.4.R1) (18) and Scimago Graphica(1.0.52) (19) were deployed.

The annual publication is one of the important indicators for evaluating the development of scientific research, and to a certain extent, it reflects the growth of knowledge in the relevant field. Over the period from 2004 to 2024, which excluded incomplete 2025 data to avoid bias in recent trends, a total of 2,416 publications related to mitophagy in neurodegenerative diseases were analyzed. As illustrated in Figure 1A, the number of published articles has exhibited a generally consistent upward trajectory, reaching a peak of 296 publications in 2021. Although subsequent years exhibited fluctuations—276 in 2022, 273 in 2023, and 286 in 2024—these may be partially attributable to database indexing delays, particularly for the more recent years (2023–2024). Nonetheless, these observations do not obscure the overall pattern of sustained growth in publication output, indicating the field’s robust academic expansion. Besides, a generalized additive model was utilized to evaluate the correlation between publication counts and the years they were published. The analysis demonstrated that the model was accurate in aligning with the yearly publication trend, as indicated by an R² of 0.9144. To investigate the temporal growth pattern of literature, the Price’s Law exponential growth model was applied to the cumulative number of publications. As shown in Figure 1B, the total number of publications exhibited a clear upward trend over time, suggesting a potential exponential growth pattern. After excluding publication data from 2025 to eliminate potential outliers or incomplete records, an exponential regression model was constructed using sequential year indices (where x = 1 corresponds to 2004, x = 2 to 2005, and so on up to x = 21 for 2024) rather than absolute years to avoid numerical scaling issues. The resulting regression equation was: y = 20.916e⁰.^2456x, with a coefficient of determination R² = 0.9665, indicating an excellent fit and underscoring accelerating interest in mitophagy’s role in ND.

A total of 105 countries contributed to research on mitophagy in neurodegenerative diseases. As shown in Figure 2A, the top 10 countries or regions by publication count are presented. The USA was the most productive country with 762 publications. Researchers from China and Italy contributed 643 and 218 articles, respectively, ranking second and third. In terms of citations illustrated in Figure 2B, the USA also led with 71,447 citations, followed by China with 24,165 citations, while the United Kingdom ranked third with 12,041 citations. Figures 2C–E illustrated the research collaborations among various countries and regions, highlighting that the majority of partnerships occur among the top research-producing countries, particularly between the USA, China, European nations such as the UK and Italy and other developed countries. Notably, the collaboration between USA and China was the most frequent, with a recorded frequency of 56 instances. This was followed by the collaborative efforts between the United States and the United Kingdom (31), and between the United States and India (25), which were respectively ranked second and third. These collaboration patterns aligned with countries’ publication outputs, suggesting that nations with strong research capabilities often took a leading role. Such leadership not only enhanced collaborative opportunities but also facilitated bidirectional knowledge transfer, particularly between established research powers and emerging scientific communities.

A total of 3,186 institutions worldwide were involved in mitophagy research in neurodegenerative diseases. Figure 3A showed the publication output of leading institutions, with the National Institutes of Health (NIH) leading with 53 publications, followed by the University of California System (49) and University College London (45). American and European institutions dominated the rankings, with notable contributions from Chinese institutions. Supplementary Table 1 provided multi-dimensional analysis beyond publication counts. Network centrality analysis revealed the Chinese Academy of Sciences as the most influential research hub (centrality = 0.19), followed by NIH (0.17), University of California System (0.14), and University College London (0.11).

Temporally, most institutions began significant contributions around 2007–2008, though the Ministry of Education of China entered later in 2014, reflecting expanding international interest. Burst analysis identified periods of intense research activity (citation), with the University of London demonstrating the highest research momentum (burst = 7.7756), followed by the Ministry of Education of China (7.3554) and University College London (6.9315). Collaboration analysis (Figure 3B) revealed a network of 485 institutions with 678 collaborative links and a density of 0.0058, indicating sparse collaboration with significant potential for expansion. Collaboration serves as a catalyst for innovation, facilitating interdisciplinary integration and knowledge exchange among institutions (20). The network structure confirmed that high-centrality institutions like NIH, University of California System, and University College London not only produced substantial research output but also served as key catalysts connecting the global research community. These findings collectively demonstrated that institutional leadership in this field encompassed publication volume, network influence, and collaborative connectivity.

Authors serve as the driving force behind scientific publication production, making the analysis of their contributions a critical indicator of field advancement (21). Among the 12,369 authors who contributed to this field, Tavernarakis Nektarios ranked first with 18 publications and 2,032 citations (h-index = 13). He investigates mitophagy dysfunction’s role in driving age-related neurodegenerative diseases like Alzheimer’s (22), and molecular links between mitophagy, cellular homeostasis, and longevity, emphasizing how maintaining mitophagic flux counters neural pathologies (23, 24). He was closely followed by Reddy, P. Hemachandra, who also had 18 publications but fewer citations (1,248, h-index = 12); Reddy, P. Hemachandra studies mitochondrial abnormalities in neurodegenerative diseases, focusing on oxidative damage from free radicals (25), fission/fusion dynamics linked to synaptic harm (e.g., Aβ-Drp1 in Alzheimer’s), and shared metabolic pathways with obesity and diabetes (26). Chu, Charleen T. ranked third with 16 publications and demonstrated higher citation influence (1,653 citations, h-index = 15), as her work specializes selective autophagy and mitophagy in neurodegenerative diseases like Parkinson’s, focusing on how impaired mitochondrial clearance contributes to neuronal damage (27). Her research explores kinase signaling and mitochondrial quality control, emphasizing neuroprotection strategies (28) (Supplementary Table 3).

The author collaboration networks (Figure 3C) revealed comprehensive insights into the structural organization of the research community. Most remarkably, one prominent collaborative cluster emerged, containing five of the top ten authors. Tavernarakis, Nektarios demonstrated the highest collaborative activity (Total Link Strength: 25), followed by Palikaras, Konstantinos (20) and Fang, Evandro F. (18), establishing these three as primary collaborative drivers. Bohr, Vilhelm A. showed moderate engagement (13), while Klionsky, Daniel J. maintained minimal connections (1). This cluster represented a powerhouse of the research field, combining high productivity with exceptional citation impact. The remaining top author, Reddy, P. Hemachandra, led a separate cluster with substantial collaborative activity (16), whereas Chu, Charleen T., Langer, Thomas, and Holzbaur, Erika L. F. operated independently (Total Link Strength: 0). Hattori, Nobutaka demonstrated minimal collaborative engagement (3). Additionally, the overlay visualization in Figure 3D revealed distinct temporal patterns when combined with the start year data from Supplementary Table 3. The clusters demonstrated varying maturity levels: early pioneers like Hattori, Nobutaka (2004), Langer, Thomas (2006), and Klionsky, Daniel J. (2009) established foundational frameworks, appearing in blue-colored zones. Researchers from the establishment phase, such as Tavernarakis, Nektarios (2013), and Palikaras, Konstantinos (2015), occupied transitional zones, reflecting their integration during the field’s expansion. Most remarkably, recent researchers Bohr, Vilhelm A. and Fang, Evandro F. (both 2017) appeared in the light-yellow zones, indicating their emergence during the latest phase of mitophagy research.

Journal analysis effectively assists researchers in identifying the most relevant publications for their studies and interests, thereby enhancing the quality of their research evaluations (29). Supplementary Table 4 listed the top 10 journals among 698 publications from various dimensions in the field. The leading contributors were International Journal of Molecular Sciences, Cells, and Autophagy, which contributed 114 (4.44%), 69 (2.69%), and 55 (2.14%) papers on mitophagy in neurodegenerative diseases, respectively.

Figure 4A showed the temporal development of the top five journals in the field, demonstrating consistent growth in recent years and reflecting an overall upward trend. Among the top 10 journals, 50% were classified as Q1 quartile and 50% as Q2 quartile. Three journals achieved impact factors greater than 5, with Autophagy standing out with an exceptional impact factor of 14.6, reflecting its significant influence in the field. Figure 4B presented the interconnections among these journals.

The listed journals covered a broad spectrum of biological and neuroscience disciplines, providing diverse platforms for publishing mitophagy research in neurodegenerative diseases. From the specialized focus of Autophagy to the comprehensive molecular perspective of Journal of Biological Chemistry, these publications collectively offered a comprehensive landscape for exploring the molecular, cellular, and neurobiological aspects of mitophagy. Frontiers in Neuroscience and Neurobiology of Disease were particularly relevant, as they directly addressed the neurological implications of mitophagy.

In terms of co-citation analysis, Figure 4C highlighted Journal of Biological Chemistry (7,919), Proceedings of the National Academy of Sciences of the United States of America (7,167), and Nature (6,127) as the most frequently co-cited journals, each having been cited more than 6,000 times. Figure 4D presented the dual-map overlay visualization depicting citation relationships between citing and cited journals. The yellow path indicated that citing publications primarily originated from journals in “molecular biology and genetics,” while cited papers predominantly derived from journals in “molecular biology and immunology.” This analysis revealed the knowledge development patterns and research directions in the field.

The central role of mitophagy in neurodegenerative diseases is primarily driven by the PINK1-Parkin pathway, which has emerged as the key framework in the field, particularly in PD. Mutations in PINK1 or Parkin impair this pathway, leading to mitochondrial dysfunction, the accumulation of ROS, and neuronal death (36). This pathway operates through a defined cascade: PINK1 accumulates on damaged mitochondria, phosphorylates ubiquitin at Ser65, and recruits Parkin to initiate the ubiquitination of outer mitochondrial membrane proteins for degradation (37).

Mitochondrial dynamics, particularly the balance between fission and fusion, plays a vital role in mitochondrial quality control and cellular function. DRP1-mediated fission segregates damaged mitochondria for mitophagy, while MFN1/2-mediated fusion allows partially dysfunctional mitochondria to recover (38). In HD, excessive mitochondrial fission, driven by mutant huntingtin, results in fragmented mitochondria and impaired energy production, while in AD, amyloid-beta and tau proteins disrupt mitochondrial dynamics, worsening mitochondrial function (38). These disruptions are especially damaging in neurons with long axons, such as dopaminergic neurons in PD and motor neurons in ALS, where fragmented mitochondria fail to efficiently deliver ATP to distal segments, leading to energy depletion and dysfunction (39). Therapeutic attempts to modulate mitochondrial dynamics have encountered challenges, as inhibitors like Mdivi-1, which target DRP1, may impair physiological fission necessary for mitophagy, highlighting the need for precision in restoring mitochondrial dynamics (39). Disruptions in calcium homeostasis, further exacerbated by mitochondrial dynamics dysfunction, complicate potential therapeutic strategies.

Proteostasis, the balance of protein folding, degradation, and clearance, is another interconnected pathway involved in mitochondrial dysfunction. The UPS tags damaged or misfolded proteins for degradation, while CMA transports specific substrates to lysosomes (40). In PD, Parkin functions as a dual E3 ubiquitin ligase, tagging both mitochondrial proteins for mitophagy and cytosolic α-synuclein for proteasomal degradation. Mutations impair the UPS, leading to the accumulation of α-synuclein and toxic aggregates (40, 41). This creates a bidirectional pathology: α-synuclein aggregates overload the UPS and inhibit CMA by blocking LAMP2A multimerization at the lysosomal membrane (42). Loss of DJ-1 function further impairs CMA, increasing α-synuclein levels and neurotoxicity, particularly in aging individuals where LAMP2A expression declines (42). In HD, mutant huntingtin disrupts CMA, impairing protein clearance and accelerating neurodegeneration. This proteostasis failure, which may involve the simultaneous impairment of the UPS, CMA, and mitophagy, suggests that HD may require multi-pathway therapeutic interventions, distinguishing it from PD, where the PINK1-Parkin pathway plays a more central role.

Mitophagy maintains neuronal homeostasis by clearing damaged mitochondria, reducing ROS, and preventing apoptosis. Yet, excessive or impaired mitophagy disrupts energy balance and synaptic function. In Parkinson’s and Alzheimer’s diseases, mutations in PINK1, Parkin, and related genes upset this balance, leading to neurodegeneration. Thus, mitophagy acts as a double-edged sword: protective when properly regulated, yet detrimental when excessive, requiring a balance that demands precise modulation to preserve mitochondrial integrity and neuronal homeostasis.

In AD, disrupted mitochondria-associated membranes (MAMs) impair mitochondrial function and promote Aβ accumulation, linking mitochondrial dysfunction to AD pathogenesis (43). Defective mitophagy exacerbates neuronal injury through enhanced Aβ and Tau aggregation, oxidative stress, and neuroinflammation (44, 45). Decreased NLRX1 expression leads to abnormal mitochondrial morphology and increased Aβ levels in APP/PS1 models, highlighting NLRX1 as a potential therapeutic target (46). Pharmacological enhancement of mitophagy, such as Remimazolam-mediated activation of the PINK1/Parkin pathway, restores mitochondrial function and reduces Aβ_1–42-induced cytotoxicity and Tau hyperphosphorylation (47). Moreover, mitochondrial aging and dysregulated dynamics (fission/fusion imbalance) contribute to bioenergetic failure and Aβ42 accumulation, while stress-induced BNIP3L upregulation may restore mitophagy efficiency (48–50). Together, these findings illustrate how mitophagy in AD can be both neuroprotective and pathogenic, depending on its degree and timing of activation.

In PD, mitophagy dysfunction is central to dopaminergic neuron degeneration. Mutations such as VPS35 p.D620N impair PINK1/Parkin-mediated mitophagy and enhance LRRK2 kinase activity, accelerating disease progression (51). Accumulation of α-synuclein at MAMs disrupts mitochondrial dynamics, further inhibiting mitophagy and promoting oxidative stress (43). Pharmacological interventions that restore mitophagy—such as Erbai decoction, FGF21, ORA471, and Asiatic acid—have been shown to alleviate mitochondrial dysfunction and improve motor performance in PD models (52–55). While moderate activation of mitophagy protects neuronal integrity, overactivation may deplete mitochondria, reinforcing the concept that mitophagy in PD must be finely balanced (56).

In HD, the accumulation of mutant huntingtin (mHTT) disrupts mitochondrial quality control, leading to bioenergetic deficits and neuronal death. Impaired mitophagy is a hallmark of HD pathology, associated with defective autophagy mechanisms and the toxic interaction between mHTT and voltage-dependent anion channel 1 (VDAC1), which hinders mitochondrial clearance (57, 58). Inhibition of ROCK2 aggravates oxidative stress and neurodegeneration, underscoring the importance of mitophagy regulation (59). Conversely, pharmacological modulation using SCH79797 can prevent 3-NP-induced mitophagy via the PINK1/ubiquitin pathway, highlighting its protective role (60). These findings indicate that controlled enhancement of mitophagy may alleviate mitochondrial dysfunction and neurodegeneration in HD, whereas its dysregulation can accelerate pathology.

In ALS, mitophagy impairment contributes to motor neuron degeneration through mitochondrial dysfunction and oxidative stress. The bioflavonoid isoginkgetin enhances PINK1/Parkin-dependent mitophagy, improving mitochondrial health and motor neuron survival (61). Conversely, inhibition of ROCK2 and loss of OPTN reduce autophagic flux, leading to ROS accumulation and neuronal injury (59, 62). Structural abnormalities and altered expression of mitophagy-related genes have been observed in SOD1-G93A mice, further linking mitophagy dysregulation to ALS progression (63). Moreover, increased m6A RNA methylation downregulates TFEB expression, impairing mitophagy, whereas TFEB overexpression rescues mitochondrial function (64). These studies reinforce the dual nature of mitophagy in ALS: essential for maintaining mitochondrial integrity yet detrimental when imbalanced.

Overall, across neurodegenerative diseases such as AD, PD, HD, and ALS, mitophagy emerges as a finely tuned but fragile process. Its precise temporal and spatial regulation determine whether it serves as a protector of neuronal homeostasis or a promoter of degeneration, underscoring the therapeutic need to calibrate rather than simply enhance or inhibit mitophagy.

Recent advances in PTMs have become a prominent focus in the study of mitophagy regulation. Ubiquitination, in particular, has been identified as a key PTM driving the recruitment of autophagy receptors like NDP52 and OPTINEURIN, which facilitate the degradation of damaged mitochondria (65). This has opened new avenues for therapeutic interventions, such as small molecules like kinetin riboside, which can activate the PINK1-Parkin pathway independently of mitochondrial depolarization (66).

Additionally, USP30, a deubiquitinase that antagonizes Parkin, represents a promising target, with inhibitors such as MTX115 undergoing clinical trials (67). Unraveling the regulatory roles of these PTMs in mitophagy and mitochondrial homeostasis opens new avenues for targeted therapy, establishing this area as a rapidly advancing research frontier in the field.

The role of the gut microbiota in modulating mitophagy has emerged as a novel research hotspot. Gut dysbiosis—imbalance in gut microbial populations—impairs intestinal barrier function, allowing bacterial lipopolysaccharides to enter the bloodstream, activating peripheral immune cells. These pro-inflammatory cytokines cross the blood-brain barrier and activate microglia, which then exhibit defective mitophagy, leading to ROS accumulation and the activation of inflammasomes (68). This creates a feedback loop, exacerbating neuronal injury.

On the other hand, beneficial microbial metabolites such as short-chain fatty acids have been shown to positively modulate mitophagy. For instance, butyrate enhances PINK1/Parkin-mediated mitophagy and alleviates symptoms in PD models (69), while urolithin A, derived from gut microbiota, induces mitophagy and improves cognitive function in AD models (70).

Future studies on mitophagy are expected to move toward multi-omics integration, spatiotemporal imaging, and translational research. Multi-omics approaches—combining genomics, proteomics, and metabolomics—will enable comprehensive mapping of mitophagy regulatory networks and their alterations across disease progression. Advances in super-resolution and live-cell imaging, such as two-photon microscopy and fluorescence lifetime imaging, will facilitate the visualization of mitochondrial dynamics in real time, offering unprecedented insights into the cellular mechanisms underlying neurodegeneration.

Furthermore, integrating artificial intelligence with systems biology modeling holds great promise for decoding the intricate regulatory networks of mitophagy and pinpointing actionable therapeutic targets. The development of mitophagy-modulating agents—such as small molecules enhancing PINK1/Parkin signaling or mitophagy-inducing peptides—represents a promising avenue for disease intervention, bridging basic research and clinical translation.

This study provides the first comprehensive bibliometric evaluation of mitophagy research in neurodegenerative diseases, offering quantitative insights into its evolution, thematic structure, and emerging trends. We have established an objective and reproducible analytical framework to identify key contributors and research clusters. However, several limitations should be acknowledged. First, reliance on the Web of Science Core Collection, Scopus, and English-language publications may introduce selection bias, potentially omitting significant contributions from non-English or non-indexed journals. Second, inconsistencies in author and institutional naming conventions, as well as publication delays, could influence bibliometric accuracy. Third, while keyword and cluster analyses effectively reveal research patterns, they cannot fully capture the nuanced conceptual depth or experimental diversity within the field. Therefore, integrating bibliometric analyses with systematic reviews and meta-analyses will offer a more holistic perspective on the evolving research landscape of mitophagy in neurodegenerative diseases.