Expression Levels Of Drp1 Research Articles

Nrf2 expression, mitochondrial fission, and neuronal apoptosis in the prefrontal cortex of methamphetamine abusers and rats

Methamphetamine (MA), a representative amphetamine-type stimulant, is one of the most abused drugs worldwide. Studies have shown that MA-induced neurotoxicity is strongly associated with oxidative stress and apoptosis. While nuclear factor E2-related factor 2 (Nrf2), an antioxidant transcription factor, is known to exert neuroprotective effects, its role in MA-induced dopaminergic neuronal apoptosis remains incompletely understood. In the present study, we explored the effects of MA on the expression levels of Nrf2, dynamin-related protein 1 (Drp1), mitofusin 1 (Mfn1), cytochrome c oxidase (Cyt-c), and cysteine aspartate-specific protease 3 (Caspase 3), as well as the correlations between Nrf2 and mitochondrial dynamics and apoptosis. Brain tissue from MA abusers was collected during autopsy procedures. An MA-dependent rat model was also established by intraperitoneal administration of MA (10 mg/kg daily) for 28 consecutive days, followed by conditioned place preference (CPP) testing. Based on immunohistochemical staining and western blot analysis, the protein expression levels of Nrf2 and Mfn1 showed a decreasing trend, while levels of Drp1, Cyt-c, and Caspase 3 showed an increasing trend in the cerebral prefrontal cortex of both MA abusers and MA-dependent rats. Notably, the expression of Nrf2 was positively associated with the expression of Mfn1, but negatively associated with the expression levels of Drp1, Cyt-c, and Caspase 3. These findings suggest that oxidative stress and mitochondrial fission contribute to neuronal apoptosis, with Nrf2 potentially playing a critical role in MA-induced neurotoxicity.

Anti-inflammatory effect of echinacoside in collagen-induced arthritis via Nrf2/Drp1 pathway.

Oxidative damage plays an important role in the progression of rheumatoid arthritis (RA). Emerging research evidence suggests that natural antioxidants may effectively ameliorate this disease. To investigate the therapeutic effect of echinacoside (ECH) in a collagen-induced arthritis (CIA) mouse model and thus elucidate the underlying molecular mechanism in RA. Collagen-induced arthritis mice were intraperitoneally administered 1% dimethyl sulfoxide (DMSO) (control) or 0.6 mg of ECH every other day for 1 month. Arthritis scores and the number of affected paws were assessed. On day 60, mice were euthanized, synovial tissue specimens were obtained, and serum interleukin (IL)-6 and IL-1â expression levels were measured. Mitochondrial morphologies, reactive oxygen species (ROS) content, expression of dynamin-related protein 1 (Drp1), IL-6, nod-like receptor protein 3 (NLRP3), kelch-like ECH-associated protein 1 (Keap1), and nuclear factor-erythroid-2-related factor 2 (Nrf2) contents in synovium were analyzed and compared between DMSOand ECH-treated CIA mice. Following ECH treatment, mitochondria of CIA-induced mice were found to be elongated, while their arthritis scores, inflammation and the number of affected paws, and the expression levels of Drp1, NLRP3, IL-6, ROS, and Keap1 were all found to be significantly reduced. Conversely, the level of antioxidant factor Nrf2 was found to be elevated. Further, mitochondrial fission was found to be inhibited in synovial tissues. Our findings validate the therapeutic efficacy of ECH in the CIA mouse model. Echinacoside may suppress oxidative stress and inhibit inflammation by regulating the Nrf2/Drp1 pathway, thus supporting its utility in the treatment of RA.

Mitochondrial Features and Expressions of MFN2 and DRP1 during Spermiogenesis in Phascolosoma esculenta.

Mitochondria can fuse or divide, a phenomenon known as mitochondrial dynamics, and their distribution within a cell changes according to the physiological status of the cell. However, the functions of mitochondrial dynamics during spermatogenesis in animals other than mammals and fruit flies are poorly understood. In this study, we analyzed mitochondrial distribution and morphology during spermiogenesis in Sipuncula (Phascolosoma esculenta) and investigated the expression dynamics of mitochondrial fusion-related protein MFN2 and fission-related protein DRP1 during spermiogenesis. The mitochondria, which were elliptic with abundant lamellar cristae, were mainly localized near the nucleus and distributed unilaterally in cells during most stages of spermiogenesis. Their major axis length, average diameter, cross-sectional area, and volume are significantly changed during spermiogenesis. mfn2 and drp1 mRNA and proteins were most highly expressed in coelomic fluid, a spermatid development site for male P. esculenta, and highly expressed in the breeding stage compared to in the non-breeding stage. MFN2 and DRP1 expression levels were higher in components with many spermatids than in spermatid-free components. Immunofluorescence revealed that MFN2 and DRP1 were consistently expressed and that MFN2 co-localizes with mitochondria during spermiogenesis. The results provide evidence for an important role of mitochondrial dynamics during spermiogenesis from morphology and molecular biology in P. esculenta, broadening insights into the role of mitochondrial dynamics in animal spermiogenesis.

Dexmedetomidine modulates mitochondrial dynamics to protect against endotoxin-induced lung injury via the protein kinase C-ɑ/haem oxygenase-1 signalling pathway

Background Endotoxin-induced acute lung injury (ALI) has a high mortality rate, and there are limited effective treatment options available. The aim of the present study was to identify if dexmedetomidine could regulate mitochondrial fusion and fission through the protein kinase C (PKC)-α/haem oxygenase (HO)-1 pathway to protect against endotoxin-induced ALI. Materials and methods Dexmedetomidine was administered by intraperitoneal injection once daily for three days prior to induction of lung injury to mice. Mice in the PKC-α inhibitor group received dexmedetomidine by intraperitoneal injection 1 h after each chelerythrine injection, and lipopolysaccharide was injected 1 h after the last dose of dexmedetomidine. The lung wet/dry weight ratio, oxidative stress, inflammatory response, and expression levels of PKC-α, Nrf2, HO-1, Mfn1, Mfn2, OPA1, Drp1, and Fis1 were determined. Results Dexmedetomidine administration attenuated lung oxidative stress, decreased inflammatory cytokines secretion, and downregulated the expression levels of Drp1 and Fis1. Moreover, dexmedetomidine increased levels of Mfn1, Mfn2, and OPA1, and alleviated endotoxin-induced lung injury. Administration of chelerythrine partially reversed the pneumoprotective effects of dexmedetomidine. Conclusions Dexmedetomidine may activate the PKC-ɑ/HO-1 pathway to increase the expression of Mfn1, Mfn2, and OPA1, while decreasing Drp1 and Fis1 expression, thereby reduce endotoxin-induced acute lung injury.

CISD1 protects against atherosclerosis by suppressing lipid accumulation and inflammation via mediating Drp1

Atherosclerosis still remains the leading cause of morbidity and mortality worldwide, and deeper understanding of target signaling that protect from the atherosclerosis progression may provide novel therapeutic strategies. CDGSH iron-sulfur domain-containing protein 1 (CISD1) is a protein localized on the outer membrane of mitochondria, and plays key roles in regulating cell death and oxidative stress. However, its potential on atherosclerosis development and the underlying mechanisms are largely unknown. Here, in our study, we found markedly decreased CISD1 expression in lipid-laden THP1 macrophages. Notably, lentivirus (LV)-mediated CISD1 over-expression remarkably ameliorated lipid deposition in macrophages stimulated by ox-LDL. Furthermore, cellular total ROS and mitochondrial ROS generation, and impairment of mitochondrial membrane potential (MMP) were highly induced by ox-LDL in THP1 cells, while being considerably reversed upon CISD1 over-expression. Inflammatory response caused by ox-LDL was also significantly restrained in macrophages with CISD1 over-expression. Mechanistically, we found that CISD1 could interact with dynamin-related protein 1 (Drp1). Intriguingly, CISD1-improved mitochondrial dysfunction and inflammation in ox-LDL-treated macrophages were strongly abolished by Drp1 over-expression, indicating that Drp1 suppression might be necessary for CISD1 to perform its protective effects in vitro. In high fat diet (HFD)-fed apolipoprotein E-deficient (ApoE−/−) mice, tail vein injection of lentiviral vector expressing CISD1 remarkably decreased atherosclerotic lesion area, serum LDL cholesterol levels and triglyceride contents. Inflammatory response, cellular total and mitochondrial ROS production, and Drp1 expression levels in aorta tissues were also dramatically ameliorated in HFD-fed ApoE−/− mice, contributing to the inhibition of atherosclerosis in vivo. Therefore, improving CISD1 expression may be a novel therapeutic strategy for atherosclerosis treatment.

Exposure effects of inhaled nickel nanoparticles on the male reproductive system via mitochondria damage

Nickel nanoparticles (Ni NPs) have a wide range of application prospects, however there is still a lack of their safety evaluation for the reproductive system. Nowadays, male reproductive health has been widely concerned for the increasing incidence of male infertility. To investigate the male reproductive toxicity induced by Ni NPs and its relation with the mitochondrial fission and mitophagy, male mice were administered with or without 5, 15, and 45 mg/kg of Ni NPs by intratracheal instillation. At the end of intervention, sex hormone level, sperm abnormality rate, pathological morphology of testis, cell apoptosis and the expression levels of Drp1, Pink1 and Parkin proteins in testis tissues were detected. The results indicated that the rate of sperm deformity and serum levels of reproductive hormones increased obviously with the increasing concentrations of Ni NPs. Testicular spermatogenic cells were damaged and the number of apoptotic cells increased significantly. Furthermore, the expressions of key proteins (Drp1, Pink1 and Parkin) related to mitochondrial fission/autophagy in testis tissues also increased after exposure to Ni NPs. Collectively, mitochondria damage may play an important role in male mice reproductive toxicity induced by the intratracheal instillation of Ni NPs.

Notch1 protects against myocardial ischaemia-reperfusion injury via regulating mitochondrial fusion and function.

Mitochondrial fusion and fission dynamic are critical to the myocardial protection against ischaemia‐reperfusion injury. Notch1 signalling plays an important role in heart development, maturation and repair. However, the role of Notch1 in the myocardial mitochondrial fusion and fission dynamic remains elusive. Here, we isolated myocardial cells from rats and established myocardial ischaemia‐reperfusion injury (IRI) model. We modulated Notch1, MFN1 and DRP1 expression levels in myocardial cells via infection with recombinant adenoviruses. The results showed that Notch1 improves the cell viability and mitochondrial fusion in myocardiocytes exposed to IRI. These improvements were dependent on the regulation of MFN1 and DRP1. On the mechanism, we found that MNF1 is transcriptionally activated by RBP‐Jk in myocardiocytes. Notch1 also improves the mitochondrial membrane potential in myocardiocytes exposed to IRI. Moreover, we further confirmed the protection of the Notch1‐MFN1/Drp1 axis on the post‐ischaemic recovery of myocardial performance is associated with the preservation of the mitochondrial structure. In conclusion, this study presented a detailed mechanism by which Notch1 signalling improves mitochondrial fusion during myocardial protection.

Effect evaluation of methylprednisolone plus mitochondrial division inhibitor-1 on spinal cord injury rats

To investigate the combination effect of methylprednisolone (MP) and mitochondrial division inhibitor-1 (Mdivi-1) on the neurological function recovery of rat spinal cord injury (SCI) model. The weight-drop method was used to establish the rat SCI model; then, rats were randomized into sham group, SCI group, MP group, Mdivi-1 group and MP+Mdivi-1 group. Motor function scores were quantified to evaluate locomotor ability; HE staining was used to assess spinal cord histopathology; tissue water content, oxidative stress, tissue mitochondrial function, neurons apoptosis, and apoptosis-related protein expression were detected. From the third day after SCI, BBB score of the MP+Mdivi-1 group was obviously higher than the other experimental groups (p < 0.05). Compared with the SCI group, tissue water content of the Mdivi-1 group and MP+Mdivi-1 group reduced obviously (p < 0.05), mitochondrial membrane potential (MMP) level and ATP content in the Mdivi-1 group and MP+Mdivi-1 group were both higher (p < 0.05). Meanwhile, three kinds of treatment all reduced apoptosis significantly, while MP plus Mdivi-1 exhibited the best inhibition effect on apoptosis (p < 0.05). The expression levels of Drp1, cytochrome c, and caspase-3 were all upregulated obviously; Mdivi-1 could inhibit Drp1 upregulation induced by SCI; for the upregulation of cytochrome c and caspase-3, the inhibition effect of Mdivi-1 approached MP. When MP combined with Mdivi-1, there was the best inhibition effect. MP combined with Mdivi-1 may produce better neurological function recovery, through improving functional status of mitochondria and inhibiting lipid peroxidation in damaged tissue of SCI rats, and thus alleviating apoptosis.

TNF-α induces Drp1-mediated mitochondrial fragmentation during inflammatory cardiomyocyte injury.

Dynamin-related peptide1 (Drpl)-mediated mitochondrial fission is an important process associated with cardiac dysfunction under different pathological conditions. The aim of the present study was to investigate the expression of Drpl during inflammatory myocardial injury. Sprague‑Dawley rats were treated intraperitoneally with lipopolysaccharides (LPS). Furthermore, cultured H9C2 cardiomyocytes were treated with LPS, interleukin‑6 (IL‑6) and tumor necrosis factor‑α (TNF‑α). Total and mitochondrial proteins were isolated from the heart tissue of rats and from the H9C2 cardiomyocytes. Expression levels of Drp1 and RhoA were analyzed by western blotting. Mitochondrial morphology was determined using confocal laser microscopy. The levels of mitochondrial Drp1 and phosphorylated‑Drp1 (p‑Drp1) Ser616 were revealed to be increased in rats 6h after injection with LPS (5, 10or20mg/kg). Furthermore, treatment with LPS and IL‑6 did not demonstrate a significant effect on the expression of total and mitochondrial Drp1 in H9C2 cardiomyocytes invitro; however, treatment with TNF‑α (20ng/ml) significantly enhanced the levels of mitochondrial Drp1 and p‑Drp1 Ser616. Following TNF‑α treatment, the expression of Ras homolog gene family memberA (RhoA) was also revealed to increase. Treatment with both Y‑27632 and fasudil, [Rho kinase (ROCK) inhibitors], was demonstrated to attenuate the otherwise TNF‑α‑induced increase in p‑Drp1 Ser616 and mitochondrial Drp1. In addition, it was revealed that Y‑27632 and fasudil may also attenuate the TNF‑α‑induced increase in mitochondrial fragmentation and cell viability. Therefore, the findings of the present study suggest that TNF‑α is the predominant inducer of Drp1 S616 phosphorylation during sepsis. The results of the present study also suggest that the RhoA/ROCK pathway may be involved in the phosphorylation and mitochondrial translocation of Drp1, which leads to mitochondrial fragmentation.

Regulation of neural stem cell fate decisions by mitochondrial dynamics.

Regulation of neural stem cell fate decisions by mitochondrial dynamics.

Drp1 regulates mitochondrial morphology and cell proliferation in cutaneous squamous cell carcinoma

BackgroundDynamin-related protein 1 (Drp1) mediates mitochondrial fission. Recently, several studies have shown that Drp1 plays an important role in some cancers. However, little is known about Drp1 in cutaneous squamous cell carcinoma (SCC). ObjectiveTo investigate the role of Drp1 in the tumorigenesis of cutaneous SCCs. Methods and resultsWe investigated cell proliferation, cell cycle, mitochondrial morphology, and MAPK signaling pathway using cutaneous SCC A431 and DJM1 cells that were transfected with shRNA vectors targeting Drp1. The Drp1 gene-knockdown SCC cells showed lower cell proliferation than scramble-control cells, as assessed by direct cell counting and clonogenic assays. DNA content analysis showed Drp1 knockdown to cause G2/M arrest. Morphologically, the depletion of Drp1 resulted in an elongated, hyper-fused mitochondrial network. The MEK inhibitor PD325901 suppressed cell proliferation, as well as inhibiting the phosphorylation of ERK1/2 and Drp1Ser616. Also, PD325901 caused the dysregulation of the mitochondrial network. In tumor xenografts of DJM1 cells, the knockdown of Drp1 suppressed tumor growth in vivo, and clinically, the expression levels of Drp1 were higher in cutaneous SCCs than in normal epidermis, and correlated positively with the advanced clinical stages. ConclusionOur results reveal a crucial function for Drp1 in regulating tumor growth, mitochondrial morphology, and cell cycle in cutaneous SCC, suggesting that Drp1 could be a novel target for skin tumor therapies.

Abstract 78: TNFR2 Stimulation Promotes Mitochondrial Fusion via Stat3 and NF-kB Dependent Activation of OPA1 Expression

Background: TNFR2 stimulation is known to possess protective effects for the cardiomyocytes, however, the underlying mechanisms remain unknown. Methods and Results: Using cultured neonatal cardiomyocytes that were infected with lentivirus containing shRNA targeting TNFR1, we showed that TNFR2 activation by TNFα (5nmol/L) resulted in increased mitochondrial fusion, mitochondrial membrane potential which were associated with both elevated intracellular ATP levels and oxygen consumption rate. Intriguingly, these changes were associated with increased protein levels of OPA1, with no changes in the expression levels of Drp1, Mfn1, Mfn2. We went further and reproduced previously reported data that NF-kB acetylation (Lys310) was increased with TNFR2 activation. Interestingly, however, we also observed dose-dependent effects on increase in Stat3 acetylation. Using shRNA approach, we then demonstrated that either Stat3 or NF-kB knockdown can attenuate TNFR2 induced OPA1 expression. The close interaction between these two signalings was validated by co-IP assay and confocal immunofluorescence staining. Aided by bio-informatics searching, we then performed ChIP assay to show that the binding sites of OPA1 promoter regions for STAT3 (-156 to -167) and NFkB (-192 to -203) were adjacent. We further validated that p300 induced Stat3 acetylation was indispensable for complex formation by the interaction between Stat3-DBD and NF-kB -ΔRHD, which in turn was a key event for OPA1 transcription activation. And silence of p300 can abolish OPA1 upregulation upon TNFR2 activation. Computerized data analysis based on zdock and zrank score followed by molecular dynamic simulation model for the whole Stat3 structure revealed higher value of the exterior dielectric constant (obtained from MM/PBSA calculation) for the two sites, K370 and K383, of Stat3, suggesting the essential roles for these two sites for Stat3-NFkB interaction, which were confirmed by co-IP with Stat3-DBD mutants (K370Q,K370R,K383Q,K383R) approach. Conclusions: Our data suggested that p300 mediated Stat3 acetylation cooperates with NF-kB to modulate TNFR2 activation induced OPA1 upregulation, leading to improved mitochondrial morphology and function.

Zhi-Long-Huo-Xue-Tong-Yu modulates mitochondrial fission through the ROCK1 pathway in mitochondrial dysfunction caused by streptozotocin-induced diabetic kidney injury.

Zhi-Long-Huo-Xue-Tong-Yu (ZLHXTY) is a defined mixture of 5 herbs developed by Professor S.J. Yang according to the Buyang Huanwu decoction method, which has been recorded in the Yilingaicuo. This study investigated the renoprotective effects of ZLHXTY on mitochondrial dysfunction induced by diabetic kidney injury in a diabetic rat model. Diabetes was induced by a single intravenous injection of streptozotocin. Rats were daily fed either ZLHXTY or vehicle beginning in the 1st week after injection. Levels of mitofusin 2 (mfn2), dynamin-related protein 1 (Drp1), caspase-9, and rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) were detected using Western blotting. Levels of intracellular calcium and adenosine triphosphate (ATP) were examined using an enzyme-linked immunosorbent assay. An electron microscopic examination of kidney tissue was performed. The levels of mfn2 and ATP in the diabetes and ZLHXTY groups decreased from the 4th week after modeling. The expression levels of Drp1, ROCK1, and caspase-9 increased in the diabetes group but decreased in the ZLHXTY group from the 4th week after modeling. Compared with the diabetes group, ZLHXTY treatment decreased the mesangial expansion index and proteinuria levels, and improved the pathological changes typical of diabetic kidney injury. Furthermore, ZLHXTY treatment inhibited the activation of ROCK1 and expression of Drp1 and caspase-9, but did not affect the expression of mfn2. This study indicates that ZLHXTY treatment could protect kidney tissue from diabetic injury through the ROCK1 pathway response to mitochondrial dysfunction induced by diabetes.

Deregulation of Mitochondria-Shaping Proteins Opa-1 and Drp-1 in Manganese-Induced Apoptosis

Mitochondria are dynamic organelles that undergo fusion and fission processes. These events are regulated by mitochondria-shaping proteins. Changes in the expression and/or localization of these proteins lead to a mitochondrial dynamics impairment and may promote apoptosis. Increasing evidence correlates the mitochondrial dynamics disruption with the occurrence of neurodegenerative diseases. Therefore, we focused on this topic in Manganese (Mn)-induced Parkinsonism, a disorder associated with Mn accumulation preferentially in the basal ganglia where mitochondria from astrocytes represent an early target. Using MitoTracker Red staining we observed increased mitochondrial network fission in Mn-exposed rat astrocytoma C6 cells. Moreover, Mn induced a marked decrease in fusion protein Opa-1 levels as well as a dramatic increase in the expression of fission protein Drp-1. Additionally, Mn provoked a significant release of high MW Opa-1 isoforms from the mitochondria to the cytosol as well as an increased Drp-1 translocation to the mitochondria. Both Mdivi-1, a pharmacological Drp-1 inhibitor, and rat Drp-1 siRNA reduced the number of apoptotic nuclei, preserved the mitochondrial network integrity and prevented cell death. CsA, an MPTP opening inhibitor, prevented mitochondrial Δψm disruption, Opa-1 processing and Drp-1 translocation to the mitochondria therefore protecting Mn-exposed cells from mitochondrial disruption and apoptosis. The histological analysis and Hoechst 33258 staining of brain sections of Mn-injected rats in the striatum showed a decrease in cellular mass paralleled with an increase in the occurrence of apoptotic nuclei. Opa-1 and Drp-1 expression levels were also changed by Mn-treatment. Our results demonstrate for the first time that abnormal mitochondrial dynamics is implicated in both in vitro and in vivo Mn toxicity. In addition we show that the imbalance in fusion/fission equilibrium might be involved in Mn-induced apoptosis. This knowledge may provide new therapeutic tools for the treatment of Manganism and other neurodegenerative diseases.

Impaired Mitochondrial Dynamics and Nrf2 Signaling Contribute to Compromised Responses to Oxidative Stress in Striatal Cells Expressing Full-Length Mutant Huntingtin

Huntington disease (HD) is an inherited neurodegenerative disease resulting from an abnormal expansion of polyglutamine in huntingtin (Htt). Compromised oxidative stress defense systems have emerged as a contributing factor to the pathogenesis of HD. Indeed activation of the Nrf2 pathway, which plays a prominent role in mediating antioxidant responses, has been considered as a therapeutic strategy for the treatment of HD. Given the fact that there is an interrelationship between impairments in mitochondrial dynamics and increased oxidative stress, in this present study we examined the effect of mutant Htt (mHtt) on these two parameters. STHdhQ111/Q111 cells, striatal cells expressing mHtt, display more fragmented mitochondria compared to STHdhQ7/Q7 cells, striatal cells expressing wild type Htt, concurrent with alterations in the expression levels of Drp1 and Opa1, key regulators of mitochondrial fission and fusion, respectively. Studies of mitochondrial dynamics using cell fusion and mitochondrial targeted photo-switchable Dendra revealed that mitochondrial fusion is significantly decreased in STHdhQ111/Q111 cells. Oxidative stress leads to dramatic increases in the number of STHdhQ111/Q111 cells containing swollen mitochondria, while STHdhQ7/Q7 cells just show increases in the number of fragmented mitochondria. mHtt expression results in reduced activity of Nrf2, and activation of the Nrf2 pathway by the oxidant tBHQ is significantly impaired in STHdhQ111/Q111 cells. Nrf2 expression does not differ between the two cell types, but STHdhQ111/Q111 cells show reduced expression of Keap1 and p62, key modulators of Nrf2 signaling. In addition, STHdhQ111/Q111 cells exhibit increases in autophagy, whereas the basal level of autophagy activation is low in STHdhQ7/Q7 cells. These results suggest that mHtt disrupts Nrf2 signaling which contributes to impaired mitochondrial dynamics and may enhance susceptibility to oxidative stress in STHdhQ111/Q111 cells.

Decreased expression of Drp1 and Fis1 mediates mitochondrial elongation in senescent cells and enhances resistance to oxidative stress through PINK1

Mitochondria display different morphologies, depending on cell type and physiological situation. In many senescent cell types, an extensive elongation of mitochondria occurs, implying that the increase of mitochondrial length in senescence could have a functional role. To test this hypothesis, human endothelial cells (HUVECs) were aged in vitro. Young HUVECs had tubular mitochondria, whereas senescent cells were characterized by long interconnected mitochondria. The change in mitochondrial morphology was caused by downregulation of the expression of Fis1 and Drp1, two proteins regulating mitochondrial fission. Targeted photodamage of mitochondria induced the formation of reactive oxygen species (ROS), which triggered mitochondrial fragmentation and loss of membrane potential in young cells, whereas senescent cells proved to be resistant. Alterations of the Fis1 and Drp1 expression levels also influenced the expression of the putative serine-threonine kinase PINK1, which is associated with the PARK6 variant of Parkinson's disease. Downregulation of PINK1 or overexpression of a PINK1 mutant (G309D) increased the sensitivity against ROS in young cells. These results indicate that there is a Drp1- and Fis1-induced, and PINK1-mediated protection mechanism in senescent cells, which, when compromised, could contribute to the age-related progression of Parkinson's disease and arteriosclerosis.