Drp1‐dependent peptide reverse mitochondrial fragmentation, a homeostatic response in Friedreich ataxia

Johnson, Joseph Taber; Mercado-Ayón, Elizabeth; Clark, Elisia; Lynch, David R.; Lin, Hong

doi:10.1002/prp2.755

Cited by 19 publications

(8 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We previously reported that FRDA patient fibroblasts displayed high amounts of fragmented mitochondrial networks, accompanied by clustering of Dynamin-related protein 1 (Drp1) phosphorylated at its (Ser616) residue at the fragmentation sites ( Johnson et al, 2021 ). Thus, to assess if frataxin knockdown manifests mechanistic similarities with in vitro experiments and leads to increases in pDrp1 in the FRDA cerebellum, we analyzed the cerebellum at different stages of induction in FRDAkd mice.…”

Section: Resultsmentioning

confidence: 99%

“…Tissue pathology was assessed by performing immunohistochemical studies following the procedure previously described ( Lin et al, 2014 ; Johnson et al, 2021 ). The paraffin-embedded brain and DRG sections were deparaffinized, rehydrated, and antigen-retrieved in antigen unmasking solution (Vector Laboratories) and then subject to the immunostaining procedure.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Cerebellar Pathology in an Inducible Mouse Model of Friedreich Ataxia

et al. 2022

Self Cite

View full text Add to dashboard Cite

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by deficiency of the mitochondrial protein frataxin. Lack of frataxin causes neuronal loss in various areas of the CNS and PNS. In particular, cerebellar neuropathology in FRDA patients includes loss of large principal neurons and synaptic terminals in the dentate nucleus (DN), and previous studies have demonstrated early synaptic deficits in the Knockin-Knockout mouse model of FRDA. However, the exact correlation of frataxin deficiency with cerebellar neuropathology remains unclear. Here we report that doxycycline-induced frataxin knockdown in a mouse model of FRDA (FRDAkd) leads to synaptic cerebellar degeneration that can be partially reversed by AAV8-mediated frataxin restoration. Loss of cerebellar Purkinje neurons and large DN principal neurons are observed in the FRDAkd mouse cerebellum. Levels of the climbing fiber-specific glutamatergic synaptic marker VGLUT2 decline starting at 4 weeks after dox induction, whereas levels of the parallel fiber-specific synaptic marker VGLUT1 are reduced by 18-weeks. These findings suggest initial selective degeneration of climbing fiber synapses followed by loss of parallel fiber synapses. The GABAergic synaptic marker GAD65 progressively declined during dox induction in FRDAkd mice, while GAD67 levels remained unaltered, suggesting specific roles for frataxin in maintaining cerebellar synaptic integrity and function during adulthood. Expression of frataxin following AAV8-mediated gene transfer partially restored VGLUT1/2 levels. Taken together, our findings show that frataxin knockdown leads to cerebellar degeneration in the FRDAkd mouse model, suggesting that frataxin helps maintain cerebellar structure and function.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Cerebellar Pathology in an Inducible Mouse Model of Friedreich Ataxia

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…SS-31 has also been reported to reverse mitochondrial fragmentation in patients with mitochondrial disease. 30,41…”

Section: Discussionmentioning

confidence: 99%

“…SS-31 has also been reported to reverse mitochondrial fragmentation in patients with mitochondrial disease. 30,41 Mitochondria are known to produce significant amounts of ROS that may contribute to intracellular oxidative stress. 56 ROS have been reported to be associated with tendon pathology, including pathologic tendon calcification, 69 and the accumulation of ROS leading to oxidative stress has been implicated as a mediator of age-related rotator cuff tendinopathy.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of SS-31 as a Potential Strategy for Tendinopathy Treatment: An In Vitro Model

Zhang

et al. 2022

Am J Sports Med

View full text Add to dashboard Cite

Background: Studies in our laboratory have demonstrated mitochondrial dysfunction in human and animal models of supraspinatus tendinopathy. SS-31 (elamipretide) has been reported to improve mitochondrial function and to be effective in clinical trials for several diseases. The potential of SS-31 in treating tendinopathy has not been explored. Hypothesis: SS-31 would improve mitochondrial function in human tenocytes sampled from patients with tendinopathy. Study Design: Controlled laboratory study. Methods: Healthy tenocytes were obtained from normal hamstring tendon biopsy specimens in 9 patients undergoing anterior cruciate ligament reconstruction, and tenocytes were collected from degenerative supraspinatus tendon biopsy specimens in 9 patients undergoing rotator cuff repair. Tenocytes were cultured, used at passage 1, and assigned to 4 groups: healthy tenocytes, healthy tenocytes with 1μM SS-31 treatment for 72 hours, degenerative tenocytes, and degenerative tenocytes with 1μM SS-31 treatment for 72 hours. The outcomes included measurements of mitochondrial potential, mitochondrial morphology by transmission electron microscopy imaging, reactive oxygen species and superoxidative dismutase activity, gene expression, and cell viability. Results: An increase in the cell fraction with depolarized mitochondria was found in degenerative tenocytes ( P = .014), followed by a decrease after SS-31 treatment ( P = .018). Transmission electron microscopy images demonstrated morphological changes with a decreased number and size of mitochondria per cell in the degenerative tenocytes ( P = .018) and with improvement after SS-31 treatment. There was no significant difference in the level of reactive oxygen species between healthy and degenerative tenocytes in culture, but superoxidative dismutase activity was significantly decreased in the degenerative group ( P = .006), which then increased after SS-31 treatment ( P = .012). These findings suggested that mitochondrial dysfunction may be reversed by SS-31 treatment. The gene expression of matrix metalloproteinase-1 (matrix remodeling, P = .029) and fatty acid–binding protein 4 (fatty infiltration, P = .046) was significantly upregulated in the degenerative tenocytes and reduced by SS-31 treatment ( P = .048; P = .007). Gene expression for hypoxia-inducible factor1 α and the proapoptotic regulator Bcl-2–associated X protein was increased in the degenerative tenocytes. There was a significant decrease in cell viability in degenerative tenocytes as compared with the healthy tenocytes, with small improvement after treatment with SS-31. Conclusion: There are changes in mitochondrial structure and function in tenocytes derived from degenerative tendons, and SS-31, as a mitochondrial protectant, could improve mitochondrial function and promote the healing of tendinopathy. Clinical Relevance: Mitochondrial dysfunction appears to play a role in the development of tendinopathy, and SS-31, as a mitochondrial protective agent, may be a therapeutic agent in the treatment of tendinopathy.

show abstract

“…In vivo models of FRDA include yeast, nematode worm, fruit fly, and mice ( Babcock et al, 1997 ; Radisky et al, 1999 ; Puccio et al, 2001 ; Al-Mahdawi et al, 2004 ; Vázquez-Manrique et al, 2006 ; Virmouni et al, 2014 ; Monnier et al, 2018 ), whereas FRDA in vitro models include patient-derived cells such as immortalized lymphoblastoid cells, primary fibroblasts ( Li et al, 2016 ; Agro and Diaz-Nido, 2020 ; Misiorek et al, 2020 ; Johnson et al, 2021 ), FRDA-derived iPSCs ( Angulo et al, 2021 ; Kelekci et al, 2021 ), and iPSC-based models such as neurons, cardiomyocytes, and beta cells ( Crombie et al, 2016 ; Schreiber et al, 2019 ) ( Figure 1 ). All these FRDA models need to imitate the symptoms of FRDA patients.…”

Section: Introductionmentioning

confidence: 99%

Perspectives on current models of Friedreich’s ataxia

Kelekçi

Yıldız

Sevinç

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Friedreich’s ataxia (FRDA, OMIM#229300) is the most common hereditary ataxia, resulting from the reduction of frataxin protein levels due to the expansion of GAA repeats in the first intron of the FXN gene. Why the triplet repeat expansion causes a decrease in Frataxin protein levels is not entirely known. Generation of effective FRDA disease models is crucial for answering questions regarding the pathophysiology of this disease. There have been considerable efforts to generate in vitro and in vivo models of FRDA. In this perspective article, we highlight studies conducted using FRDA animal models, patient-derived materials, and particularly induced pluripotent stem cell (iPSC)-derived models. We discuss the current challenges in using FRDA animal models and patient-derived cells. Additionally, we provide a brief overview of how iPSC-based models of FRDA were used to investigate the main pathways involved in disease progression and to screen for potential therapeutic agents for FRDA. The specific focus of this perspective article is to discuss the outlook and the remaining challenges in the context of FRDA iPSC-based models.

show abstract

Drp1‐dependent peptide reverse mitochondrial fragmentation, a homeostatic response in Friedreich ataxia

Cited by 19 publications

References 40 publications

Cerebellar Pathology in an Inducible Mouse Model of Friedreich Ataxia

Cerebellar Pathology in an Inducible Mouse Model of Friedreich Ataxia

Evaluation of SS-31 as a Potential Strategy for Tendinopathy Treatment: An In Vitro Model

Perspectives on current models of Friedreich’s ataxia

Contact Info

Product

Resources

About