Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging Perspective
Mitochondria plays privotal role in diverse pathways that regulate cellular function and survival, and have emerged as a prime focus in aging and age-associated motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Accumulating evidence suggests...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-04-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/4/1065 |
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| author | Manohar Kodavati Haibo Wang Muralidhar L. Hegde |
| author_facet | Manohar Kodavati Haibo Wang Muralidhar L. Hegde |
| author_sort | Manohar Kodavati |
| collection | DOAJ |
| description | Mitochondria plays privotal role in diverse pathways that regulate cellular function and survival, and have emerged as a prime focus in aging and age-associated motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Accumulating evidence suggests that many amyloidogenic proteins, including MND-associated RNA/DNA-binding proteins fused in sarcoma (FUS) and TAR DNA binding protein (TDP)-43, are strongly linked to mitochondrial dysfunction. Animal model and patient studies have highlighted changes in mitochondrial structure, plasticity, replication/copy number, mitochondrial DNA instability, and altered membrane potential in several subsets of MNDs, and these observations are consistent with the evidence of increased excitotoxicity, induction of reactive oxygen species, and activation of intrinsic apoptotic pathways. Studies in MND rodent models also indicate that mitochondrial abnormalities begin prior to the clinical and pathological onset of the disease, suggesting a causal role of mitochondrial dysfunction. Our recent studies, which demonstrated the involvement of specific defects in DNA break-ligation mediated by DNA ligase 3 (LIG3) in FUS-associated ALS, raised a key question of its potential implication in mitochondrial DNA transactions because LIG3 is essential for both mitochondrial DNA replication and repair. This question, as well as how wild-type and mutant MND-associated factors affect mitochondria, remain to be elucidated. These new investigation avenues into the mechanistic role of mitochondrial dysfunction in MNDs are critical to identify therapeutic targets to alleviate mitochondrial toxicity and its consequences. In this article, we critically review recent advances in our understanding of mitochondrial dysfunction in diverse subgroups of MNDs and discuss challenges and future directions. |
| first_indexed | 2024-03-10T20:15:41Z |
| format | Article |
| id | doaj.art-a3099f3d1d0c4476a0f2e24d235099b0 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T20:15:41Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-a3099f3d1d0c4476a0f2e24d235099b02023-11-19T22:37:40ZengMDPI AGCells2073-44092020-04-0194106510.3390/cells9041065Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging PerspectiveManohar Kodavati0Haibo Wang1Muralidhar L. Hegde2Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX 77030, USADepartment of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX 77030, USADepartment of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX 77030, USAMitochondria plays privotal role in diverse pathways that regulate cellular function and survival, and have emerged as a prime focus in aging and age-associated motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Accumulating evidence suggests that many amyloidogenic proteins, including MND-associated RNA/DNA-binding proteins fused in sarcoma (FUS) and TAR DNA binding protein (TDP)-43, are strongly linked to mitochondrial dysfunction. Animal model and patient studies have highlighted changes in mitochondrial structure, plasticity, replication/copy number, mitochondrial DNA instability, and altered membrane potential in several subsets of MNDs, and these observations are consistent with the evidence of increased excitotoxicity, induction of reactive oxygen species, and activation of intrinsic apoptotic pathways. Studies in MND rodent models also indicate that mitochondrial abnormalities begin prior to the clinical and pathological onset of the disease, suggesting a causal role of mitochondrial dysfunction. Our recent studies, which demonstrated the involvement of specific defects in DNA break-ligation mediated by DNA ligase 3 (LIG3) in FUS-associated ALS, raised a key question of its potential implication in mitochondrial DNA transactions because LIG3 is essential for both mitochondrial DNA replication and repair. This question, as well as how wild-type and mutant MND-associated factors affect mitochondria, remain to be elucidated. These new investigation avenues into the mechanistic role of mitochondrial dysfunction in MNDs are critical to identify therapeutic targets to alleviate mitochondrial toxicity and its consequences. In this article, we critically review recent advances in our understanding of mitochondrial dysfunction in diverse subgroups of MNDs and discuss challenges and future directions.https://www.mdpi.com/2073-4409/9/4/1065mitochondriaFUSmotor neuron diseaseamyotrophic lateral sclerosisfrontotemporal dementiaDNA damage |
| spellingShingle | Manohar Kodavati Haibo Wang Muralidhar L. Hegde Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging Perspective Cells mitochondria FUS motor neuron disease amyotrophic lateral sclerosis frontotemporal dementia DNA damage |
| title | Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging Perspective |
| title_full | Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging Perspective |
| title_fullStr | Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging Perspective |
| title_full_unstemmed | Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging Perspective |
| title_short | Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging Perspective |
| title_sort | altered mitochondrial dynamics in motor neuron disease an emerging perspective |
| topic | mitochondria FUS motor neuron disease amyotrophic lateral sclerosis frontotemporal dementia DNA damage |
| url | https://www.mdpi.com/2073-4409/9/4/1065 |
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