Research has demonstrated that the regulation of mitochondrial division by Drp1 is modulated by PTM, notably the phosphorylation status of Drp1. Phosphorylation at two key serine sites, S616 (Gao et al., 2022) and S637 (Hu et al., 2023), is pivotal in modulating Drp1’s activity. The phosphorylation of Drp1 at serine 616 augments its activity, facilitating its translocation from the cytoplasm to the outer mitochondrial membrane and its interaction with receptor proteins such as Mff and Fis1 (Parida et al., 2023). This process induces mitochondrial division in the medial region, a phenomenon typically associated with normal cellular growth and metabolic requirements, thereby contributing to the equitable distribution of mitochondria within the cell (Chang et al., 2022). Phosphorylation at serine 637 resulted in the inhibition of Drp1 activity and decreased its localization to the outer mitochondrial membrane, thereby impeding mitochondrial fission (Sun et al., 2024). In the context of peripheral division, the phosphorylation of Ser637 may serve a protective role for mitochondria against excessive division by inhibiting the overactivation of Drp1. This mechanism thereby contributes to the preservation of mitochondrial network integrity (Sun et al., 2024). However, recent research indicates that the phosphorylation of Ser637 may indirectly facilitate the phosphorylation of Ser616 via a complex mechanism, thereby modulating mitochondrial division (Valera-Alberni et al., 2021). For instance, under ischemia-hypoxia conditions, there is a notable increase in the phosphorylation of Ser637, which is subsequently followed by a significant elevation in the phosphorylation of Ser616. This observation implies that Ser637 may indirectly facilitate the phosphorylation of Ser616 through an underlying mechanism (Duan et al., 2023).

The phosphorylation of Drp1 is finely regulated by multiple protein kinases. The activity of Drp1 is mainly regulated by phosphorylation at Ser616 and Ser637. The Cyclin B1/Cyclin-dependent kinase 1 (Cyclin B1/Cdk1) complex phosphorylates the Ser616 site of Drp1 and promotes its translocation in mitochondria (Cai P. et al., 2024). Similarly, Protein kinase B (Akt) promotes mitochondrial fission by directly phosphorylating the S616 site of Drp1 (Liao et al., 2024). Furthermore, PINK1 (PTEN-induced kinase 1) has been demonstrated to phosphorylate Drp1 at the Ser616 residue, thereby modulating mitochondrial fission. This process subsequently influences neuronal synaptic development and plasticity (Gao et al., 2022). Conversely, phosphorylation at Ser637 inhibited the activity of Drp1 and reduced its accumulation in the outer membrane of mitochondria, thus inhibiting mitochondrial fission. For instance, AMP-activated protein kinase (AMPK) increases the phosphorylation of Ser637 on Drp1, which inhibits mitochondrial fission, and it also prevents alterations in the morphology of the ER and mitochondria (Hu et al., 2024). In a similar way, protein kinase A (PKA) inhibits the GTPase activity of Drp1 by directly phosphorylating the S637 site at Drp1, thereby preventing mitochondrial fission and preserving the integrity of the mitochondrial structure (Cai P. et al., 2024). Additionally, Calcineurin dephosphorylates Drp1 at Ser637 and inhibits its activity, thereby reducing mitochondrial fission, a process that plays an important role in cellular stress and injury. This conclusion was confirmed in a mouse model of hippocampal injury caused by hepatic ischemia-reperfusion. Calcineurin activation led to Drp1 dephosphorylation and its movement to mitochondria, worsening mitochondrial fission and neuronal apoptosis. Treatment with the Calcineurin inhibitor FK506 increased Drp1 phosphorylation, prevented its mitochondrial translocation, and reduced mitochondrial fission (Yu et al., 2019).

In addition to phosphorylation, Drp1 is regulated by other post-translational modifications such as ubiquitination, SUMOylation, and O-GlcNAcylation, which collectively fine-tune Drp1 activity and mitochondrial fission.

Ubiquitination modification of Drp1 Ubiquitination of Drp1 mainly occurs on its lysine residues, with key sites identified as Lys38 and Lys616, with Lys38 being more commonly ubiquitinated (Li D. et al., 2024). Membrane-Associated RING-CH 5 (MARCH-V), an E3 ubiquitin ligase situated in the outer mitochondrial membrane, selectively targets Drp1 by interacting with Lys38 on the protein (Verhoeven et al., 2023). This interaction enables MARCH-V to transfer ubiquitin to Drp1, marking it for degradation and thereby negatively regulating Drp1’s activity (Karbowski et al., 2007).

SUMOylation modification of Drp1 Unlike ubiquitination, SUMOylation does not mark the protein for degradation, but can modify its function or position at variable regions of Drp1. Among them, SUMO1 coupling promotes the binding of Drp1 to the mitochondrial membrane, thereby enhancing mitochondrial fission (Wasiak et al., 2007). In contrast, SUMO2 and SUMO3 decrease this binding, attenuating mitochondrial fission (Guo et al., 2013). The intricate regulation of SUMOylation on Drp1 depends on the specific cytoplasmic conditions. This modification is crucial during cellular stress, like oxidative stress or hypoxia, as SUMOylation regulates Drp1 activity to maintain mitochondrial balance (Das and Chakrabarti, 2024).

O-GlcNAc glycosylation modification of Drp1 O-GlcNAcylation represents a dynamic post-translational modification that modulates protein function, stability, and subcellular localization. OGlcN acylation of Drp1 is particularly pronounced in both cultured neonatal cardiomyocytes and type 2 diabetic mouse hearts (Gawlowski et al., 2012). Research indicates that O-GlcNAc modification potentially regulates Drp1 activity and mitochondrial fission by influencing its phosphorylation state or interacting synergistically with other post-translational modifications (Li D. et al., 2024). Notably, OGlcN acylation of Drp1 appears to have a contributory effect on the increase in Ser616 phosphorylation and subsequent translocation of Drp1 to mitochondria (Hu et al., 2020).

In summary, Drp1 activity is regulated by a multitude of intricate factors. Given the diversity of mitochondrial fission, it is challenging for a single post-translational modification to fully account for its effects on both physiological and pathological conditions. Conversely, multiple post-translational modifications of Drp1 may have synergistic or cumulative effects. Consequently, simultaneous assessment of multiple post-translational modifications in a specific cellular environment can provide insight into the relative objectivity of mitochondrial division activation, which is thought to be a major determinant of functional outcome (Figure 2).

Mitochondria play a pivotal role in orchestrating cellular energy metabolism and maintaining calcium homeostasis. Impairment of mitochondrial function is intrinsically linked to the pathogenesis of numerous neurodegenerative disorders (Bertholet et al., 2016), including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s Disease (HD). Notably, Drp1 may be involved in the processes that cause mitochondrial fragmentation and abnormal mitochondrial dynamics in neurodegenerative diseases (Reddy et al., 2011).

AD is a neurodegenerative disorder marked by memory loss and cognitive decline, with key features being extracellular β-amyloid (Aβ) deposits and intracellular neurofibrillary tangles from Tau protein hyperphosphorylation (Liang et al., 2025). Early AD is distinguished by oxidative stress and ER stress as its distinguishing metabolic features (Placido et al., 2015; Aliev et al., 2014). Notably, mitochondrial dysfunction is well-established as a potential driver of the above events and is a prime therapeutic target for early AD lesions (Morton et al., 2021). Basic experiments have also confirmed that mitochondrial dysfunction is an early event in AD (Hauptmann et al., 2009). In the hippocampi of AD mouse models, increased levels of fission proteins like Drp1 and Fis1 and decreased levels of fusion proteins like Mfn1, Mfn2, and Opa1 were observed, suggesting disrupted mitochondrial dynamics in these models (Kandimalla et al., 2018; Manczak et al., 2018). Recent evidence underscores the crucial role of mitochondrial dysfunction, particularly abnormal fission by Drp1, in AD development and progression (Guo et al., 2018). Excessive mitochondrial fission, driven by Drp1, is a hallmark of AD, leading to β-amyloid precursor protein cleaving enzyme 1 (BACE1) activation and Aβ accumulation in the N2a cell AD model transfected with the mutant β-amyloid precursor protein (AβPP) gene (Reddy et al., 2018). Mdivi-1, a Drp1 inhibitor, has been shown to significantly improve learning and memory in APP/PS1 mice, by preventing mitochondrial fragmentation, reducing BACE1 expression and Aβ deposition in the brain (Baek et al., 2017), highlighting Drp1’s key role in Aβ production.

PD is the second most common fast-progressing neurodegenerative disorder, affecting over 6 million people worldwide (Dorsey et al., 2018). It is mainly marked by impaired automatic movement control, like balance and gait, due to degeneration of dopaminergic neurons in the substantia nigra pars compacta of the midbrain (Ponsoni et al., 2023). The pathological mechanism of this condition encompasses the abnormal aggregation of α-synuclein (α-syn), mitochondrial dysfunction, and the generation of oxidative stress (Ye et al., 2023). In transgenic murine models, α-syn pathology is correlated with alterations in Drp1 functionality and aberrant mitochondrial morphology (Banerjee et al., 2022). Research indicates that abnormal α-synuclein aggregation activates Drp1, promoting its phosphorylation at Ser616 and increasing mitochondrial fission. This excessive division damages mitochondrial integrity, leading to dysfunction that impacts neuronal energy metabolism and synaptic function (Portz and Lee, 2021). Furthermore, α-synuclein induces mitochondrial fragmentation through a Drp-1-dependent mechanism, while overexpression of the fusion protein Opa-1 counteracts this fragmentation and cytotoxicity. Drp1-mediated abnormal mitochondrial division is a critical factor in dopaminergic neuronal apoptosis. Knocking down Drp1 inhibits this aberrant division and apoptosis, leading to significant symptomatic improvements in PD mouse models (Zhang et al., 2019).

In HD, the mutant Huntington protein (mHtt) interacts with Drp1, stimulating its activity and causing excessive mitochondrial fission and distribution abnormalities, which in turn disrupt axonal transport and contribute to synaptic degeneration (Sawant et al., 2021). Mitochondrial dysfunction, resulting from the aberrant activation of Drp1 by mutant huntingtin (mHtt), not only impairs neuronal energy metabolism but also exacerbates neuronal damage through the induction of oxidative stress and disruption of calcium homeostasis.

As a major energy-demanding organ, the heart is extremely dependent on mitochondrial energy supply to maintain cardiac contraction and cardiomyocyte metabolism (Serasinghe and Chipuk, 2017). Accumulating evidence indicates that disruptions in mitochondrial dynamics may result in inadequate myocardial energy supply, serving as a significant mechanism contributing to the increased incidence of CVDs (Cho et al., 2013). Mitochondrial fission is crucial for cellular homeostasis, but in cardiovascular disease, there is often increased fission and reduced fusion (Forte et al., 2021). This indicates a strong link between Drp1-driven mitochondrial fission and impaired mitochondrial dynamics. Consequently, regulating abnormal mitochondrial fission could be an effective strategy for reducing the risk of coronary heart disease (CHD), hypertension and heart failure.

CHD is heart disease caused by ischemia, hypoxia, or necrosis of the myocardium due to coronary atherosclerosis. Myocardial ischemia and myocardial infarction, resulting from coronary atherosclerosis, can induce myocardial cell damage and necrosis, ultimately leading to diminished cardiac function and heart failure (Ajoolabady et al., 2024). CHD is the result of atherosclerosis involving the coronary arteries, with studies indicating that excessive Drp1 activation in atherosclerosis causes mitochondrial fission, increased reactive oxygen species, and impaired mitochondrial function, ultimately resulting in VSMCs necroptosis and vulnerable plaque formation (Li X. et al., 2024). Research suggests that mitochondrial fission proteins like Drp1 and Mff become more active in cardiac hypertrophy and heart failure, while the fusion protein Opa1 activity diminishes, indicating an imbalance towards excessive fission within cardiomyocytes (Adaniya et al., 2019). Furthermore, Mfn2 expression is downregulated in mouse hearts 1 and 3 weeks after aortic constriction,as well as in 10-month-old spontaneously hypertensive rats with cardiac hypertrophy (Fang et al., 2007). A separate investigation revealed that in both humans and dogs with heart failure, cardiomyocytes display reduced levels of Mfn2 and Opa1, alongside an increase levels of Drp1 and Fis1 (Sabbah et al., 2018). This evidence collectively points to a dysregulation of mitochondrial dynamics characterized by an imbalance towards fission in the pathophysiology of heart disease.

Metabolic diseases are a group of disorders characterized by hyperglycemia, obesity, insulin resistance (IR), and dyslipidemia (Hu and Jia, 2021). Mitochondria, as highly sensitive organelles, undergo fusion, fission and metabolic adaptations in response to changes in the internal and external environment. Studies indicate that mitochondrial dysfunction induces metabolic disorders, leading to the development of metabolic diseases including type 2 diabetes mellitus (T2DM) and obesity (Wada and Nakatsuka, 2016; Pinti et al., 2019).

T2DM is a progressive metabolic disorder that arises from compromised insulin responsiveness in specific target tissues, including the liver (Ling et al., 2020), skeletal muscle (Liu et al., 2014), and adipose tissue (Boengler et al., 2017), alongside inadequate insulin synthesis by pancreatic β-cells (L'Heveder and Nolan, 2013). Accumulating evidence indicates abnormal mitochondrial function is a key mechanism for pancreatic β-cell dysfunction. This dysfunction is strongly associated with reduced mitochondrial membrane potential and expression levels of key regulators of mitochondrial dynamics such as Opa1 or Mfn (Hong et al., 2018). Endothelial dysfunction in diabetes has been linked to altered mitochondrial dynamics, particularly increased fission, which is a significant contributor to this dysfunction (Shenouda et al., 2011). Studies have demonstrated that silencing the Fis1 or Drp1 genes can protect against high glucose-induced inhibition of endothelial-type nitric oxide synthase (eNOS) activity, which is hypothesized to be achieved by reducing mitochondrial reactive oxygen species (ROS) production (Kluge et al., 2013). Clinical studies have shown that the mitochondrial dynamics of diabetic patients are significantly impaired, in which Mfn2 is involved in mitochondrial fusion and is inhibited in the muscles of obese or T2DM patients (Sebastian et al., 2012). In the ApoE-knockout diabetic mouse model, Drp1-mediated mitochondrial fission inhibition through AMPK activation improves endothelial dysfunction and delays atherosclerosis (Wang et al., 2017; Liu et al., 2019). Further studies confirmed the reduction of mitochondrial fission in diabetic mice using a potent and selective Drp1 inhibitor (Wang et al., 2017), indicating that Drp1-targeted inhibition of mitochondrial fission could be a promising therapeutic strategy for managing vascular complications in diabetic patients.

The study revealed that Resistin gene humanized mouse, after 3 months of high-fat diet, there was an increase in the number of fragmented and shortened mitochondria in skeletal muscle, resulting in reduced ATP production and mitochondrial dysfunction. Moreover, the inhibition of mitochondrial division has been shown to enhance muscle insulin signaling and overall insulin sensitivity in obese mice (Jheng et al., 2012). The presented data provide compelling evidence suggesting that Drp1-mediated mitochondrial fission may contribute to the development of insulin resistance. Consequently, targeting the upstream mechanisms of Drp1 also emerges as a potential therapeutic target for obesity-related metabolic diseases.

Exercise interventions modulate Drp1 activity and curtail excessive mitochondrial fission via multiple mechanisms. Specifically, aerobic exercise diminishes mitochondrial fission by engaging AMPK and SIRT1 signaling, which inhibits Drp1 phosphorylation at Ser616, thus reducing its activity (Pedrera et al., 2025). Moreover, In an Alzheimer’s disease model, aerobic exercise suppresses Drp1 activity via miR-34a upregulation, decreasing excessive mitochondrial fission, enhancing mitochondrial function, and mitigating neuronal injury (Liu et al., 2024).

Exercise, including aerobic and resistance training, is a potent non-pharmacological strategy against neurodegenerative diseases, reducing disease markers, fostering neurogenesis, and boosting cognitive abilities. Public health efforts should focus on exercise programs for the elderly to prevent AD, PD, and HD (Gutierre et al., 2024). Moderate exercise is beneficial for cognition and AD risk reduction (Valenzuela et al., 2020). Both aerobic and resistance training are effective for cognitive enhancement in older adults, with additional benefits from cognitive-motor dual-task training (Akalp et al., 2024; Montero-Odasso et al., 2023). Aerobic exercise stabilizes sensorimotor network progression in PD patients, improving cognitive functions, and high-intensity treadmill training enhances gait in mild to moderate PD (Johansson et al., 2022; Duchesne et al., 2015). Additionally, home-based exercise significantly improves motor function in HD patients (Al-Wardat et al., 2022).

PGC-1α/Drp1 pathway Research suggests that decreased PGC-1α is associated with the onset of various neurodegenerative diseases, and its upregulation in the hippocampus is crucial for preserving neuronal mitochondrial homeostasis by reducing excessive fission and promoting fusion (Panes et al., 2022). Therefore, upregulation of PGC-1α expression may be an effective therapeutic strategy. Moderate-intensity treadmill exercise in rats with Aβ1-42-induced impairment has been demonstrated to improve spatial learning and memory, likely due to the activation of AMPK and elevated PGC-1α levels in skeletal muscle. The role PGC-1α is pivotal as it directly suppresses Drp1, decreasing mitochondrial fission and fostering mitochondrial biogenesis and functionality (Buler et al., 2014). In essence, exercise positively impacts neurodegenerative diseases by regulating the PGC-1α/Drp1 pathway, enhancing mitochondrial function, and reducing excessive mitochondrial division, supporting its use as a treatment.

Exercise modulates mitochondrial functionality via multifaceted mechanisms, mitigates oxidative stress and apoptosis, thereby exerting a protective influence against cardiovascular pathogenesis. For instance, High-intensity interval training (HIIT) significantly increased mitochondrial respiratory capacity and muscle strength in both young and elderly subjects, ameliorating the age-related decline in cardiomyocytes mitochondrial function (He et al., 2024). Endurance exercise, such as swimming, has been shown to elicit alterations in the mitochondrial life cycle, including modifications in Drp1-mediated mitochondrial fission signaling, thereby enhancing mitochondrial function in cardiomyocytes (Moore et al., 2019).

MiR-30B/p53/Drp1 pathway MiR-30B, a non-coding RNA, inhibits p53 expression, which in turn reduces Bax levels and alleviates cardiomyocyte apoptosis (Hong et al., 2024). In addition, MiR-30B can also reduce the Bax mediated apoptosis by inhibiting the activity of Drp1, reducing mitochondrial fission and maintaining the health of mitochondria (Li SN. et al., 2023). Elevated cardiomyocyte apoptosis serves as a significant indicator of the progression of chronic cardiovascular diseases and is intricately associated with various pathological processes, such as myocardial ischemia, myocardial infarction, heart failure, and atherosclerosis (Cai K. et al., 2024). Exercise potently elevates the expression of miR-30B, which in turn represses the levels of p53 and Drp1 proteins. This regulatory mechanism contributes to the preservation of mitochondrial homeostasis within cardiomyocytes, curbing excessive mitochondrial fission and thus mitigating cardiomyocyte apoptosis (Hong et al., 2024). In addition, aerobic exercise confers cardioprotection against myocardial ischemia-reperfusion injury by modulating mitochondrial dynamics—upregulating Mfn1 and Mfn2 expression and downregulating Drp1 to adjust the fission-fusion balance, thereby reducing reducing myocardial cell apoptosis (Ghahremani et al., 2018).

mTORC1/Drp1 pathway Mammalian target of rapamycin complex 1 (mTORC1) is a major regulatory molecule of cell growth and metabolism, which is involved in the regulation of protein synthesis, lipid synthesis, and autophagy, among which the activation of mTORC1 can inhibit mitophagy (Shimobayashi and Hall, 2014). In addition, Drp1 activation inhibits Parkin expression via Clec16a, reducing mitochondrial autophagy in ischemic vessels (Pedrera et al., 2025). It has been proven that aerobic exercise can inhibit the activity of mTORC1 by activating AMPK (AMP-activated protein kinase), thereby promoting mitophagy to remove damaged mitochondria. In models of heart failure, aerobic exercise reduces mitochondrial fission, improves mitochondrial function, and reduces cardiomyocyte injury by regulating mTORC1/Drp signaling (Chung et al., 2024).

Currently, both aerobic exercise and resistance training are recommended as first-line exercise therapies for T2DM. Aerobic exercise, which increases maximal oxygen uptake (Boule et al., 2003), reduces obesity (Khalafi et al., 2023)and improves blood pressure (Xi et al., 2021), is an effective strategy to increase the body’s energy requirements and simultaneously enhance insulin sensitivity and fat oxidation. Muscle is one of the most important target tissues of insulin, and muscle weakness and low muscle mass are common in patients with T2DM. A recent study has discovered that after 12 weeks of isolated centrifugal and concentric knee extensor resistance training among healthy elderly males aged 60–76, and centrifugal exercise training was found to exert a significant effect in improving insulin sensitivity, making it an effective approach for the prevention and treatment of T2DM (Chen et al., 2017). Clinical trials have shown that aerobic interval training improves glycemic control to a greater extent in patients with T2DM (Mitranun et al., 2014). It was confirmed that aerobic exercise reduced the levels of Fis1 and Parkin in skeletal muscle of sedentary adults, while increasing the ratio of fusion to fission proteins and promoting a more integrated tubulin network (Axelrod et al., 2019). These alterations were positively associated with the enhanced insulin sensitivity and substrate utilization observed after exercise training. Another study demonstrated that a 12-week aerobic exercise significantly reduced body weight, improved peripheral insulin sensitivity and fat oxidation in obese adults and was positively correlated with reduced levels of phosphorylation at the Ser616 site of Drp1 (Fealy et al., 2014). This confirms that Drp1-mediated mitochondrial fission is reduced after exercise training, suggesting that the downregulation of Drp1 activity may play a crucial role in enhancing insulin resistance in skeletal muscle.