Temporal Changes in Mitochondria-Centric Excitotoxic Responses Following Severe Penetrating Traumatic Brain Injury
<b>Background/Objectives:</b> Traumatic brain injury (TBI) remains a significant and urgent medical concern for the US military. TBI triggers excitotoxic responses immediately, involving mitochondrial dysfunction characterized by loss of calcium (Ca<sup>2+</sup>) cycling, mem...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-06-01
|
| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/13/7/1520 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849407547111374848 |
|---|---|
| author | Hiren R. Modi Sudeep Musyaju Anke H. Scultetus Jignesh D. Pandya |
| author_facet | Hiren R. Modi Sudeep Musyaju Anke H. Scultetus Jignesh D. Pandya |
| author_sort | Hiren R. Modi |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> Traumatic brain injury (TBI) remains a significant and urgent medical concern for the US military. TBI triggers excitotoxic responses immediately, involving mitochondrial dysfunction characterized by loss of calcium (Ca<sup>2+</sup>) cycling, membrane damage and increased cell death. However, a comprehensive understanding of mitochondria-centric excitotoxic responses over time has yet to be fully demonstrated after severe TBI. The current study evaluated mitochondria-centric time course responses between 30 min and 2 weeks (seven time points) after penetrating TBI (pTBI). <b>Methods</b>: Anesthetized adult male Sprague-Dawley rats were subjected to either 10% unilateral pTBI or Sham craniectomy. Animals were euthanized at various time points, and mitochondria were isolated from the injury core. <b>Results</b>: Post-injury mitochondrial Ca<sup>2+</sup> homeostasis was significantly compromised in pTBI compared to the Sham group. In parallel, mitochondrial membrane integrity markers, including cytochrome c (Cyt C) and voltage-dependent anion channel (VDAC), showed significant reduction over time post-pTBI. Apoptosis-responsive markers, such as glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and B-cell lymphoma 2 (Bcl-2), exhibited elevated responses over time post-pTBI. <b>Conclusions</b>: Our results demonstrate profound insights into elevated excitotoxic mitochondrial damage after severe TBI. This time course study uncovers novel mitochondrial targets involved in TBI excitotoxicity and offers mitigation opportunities to alleviate excitotoxic responses after penetrating TBI. |
| format | Article |
| id | doaj-art-e499b8f2a667475994015928151f5e1f |
| institution | Kabale University |
| issn | 2227-9059 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj-art-e499b8f2a667475994015928151f5e1f2025-08-20T03:36:02ZengMDPI AGBiomedicines2227-90592025-06-01137152010.3390/biomedicines13071520Temporal Changes in Mitochondria-Centric Excitotoxic Responses Following Severe Penetrating Traumatic Brain InjuryHiren R. Modi0Sudeep Musyaju1Anke H. Scultetus2Jignesh D. Pandya3Brain Trauma Neuroprotection Branch, Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD 20910, USABrain Trauma Neuroprotection Branch, Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD 20910, USABrain Trauma Neuroprotection Branch, Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD 20910, USABrain Trauma Neuroprotection Branch, Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD 20910, USA<b>Background/Objectives:</b> Traumatic brain injury (TBI) remains a significant and urgent medical concern for the US military. TBI triggers excitotoxic responses immediately, involving mitochondrial dysfunction characterized by loss of calcium (Ca<sup>2+</sup>) cycling, membrane damage and increased cell death. However, a comprehensive understanding of mitochondria-centric excitotoxic responses over time has yet to be fully demonstrated after severe TBI. The current study evaluated mitochondria-centric time course responses between 30 min and 2 weeks (seven time points) after penetrating TBI (pTBI). <b>Methods</b>: Anesthetized adult male Sprague-Dawley rats were subjected to either 10% unilateral pTBI or Sham craniectomy. Animals were euthanized at various time points, and mitochondria were isolated from the injury core. <b>Results</b>: Post-injury mitochondrial Ca<sup>2+</sup> homeostasis was significantly compromised in pTBI compared to the Sham group. In parallel, mitochondrial membrane integrity markers, including cytochrome c (Cyt C) and voltage-dependent anion channel (VDAC), showed significant reduction over time post-pTBI. Apoptosis-responsive markers, such as glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and B-cell lymphoma 2 (Bcl-2), exhibited elevated responses over time post-pTBI. <b>Conclusions</b>: Our results demonstrate profound insights into elevated excitotoxic mitochondrial damage after severe TBI. This time course study uncovers novel mitochondrial targets involved in TBI excitotoxicity and offers mitigation opportunities to alleviate excitotoxic responses after penetrating TBI.https://www.mdpi.com/2227-9059/13/7/1520severe traumatic brain injurytime coursemitochondrial damageexcitotoxicitycalcium homeostasiscell death |
| spellingShingle | Hiren R. Modi Sudeep Musyaju Anke H. Scultetus Jignesh D. Pandya Temporal Changes in Mitochondria-Centric Excitotoxic Responses Following Severe Penetrating Traumatic Brain Injury Biomedicines severe traumatic brain injury time course mitochondrial damage excitotoxicity calcium homeostasis cell death |
| title | Temporal Changes in Mitochondria-Centric Excitotoxic Responses Following Severe Penetrating Traumatic Brain Injury |
| title_full | Temporal Changes in Mitochondria-Centric Excitotoxic Responses Following Severe Penetrating Traumatic Brain Injury |
| title_fullStr | Temporal Changes in Mitochondria-Centric Excitotoxic Responses Following Severe Penetrating Traumatic Brain Injury |
| title_full_unstemmed | Temporal Changes in Mitochondria-Centric Excitotoxic Responses Following Severe Penetrating Traumatic Brain Injury |
| title_short | Temporal Changes in Mitochondria-Centric Excitotoxic Responses Following Severe Penetrating Traumatic Brain Injury |
| title_sort | temporal changes in mitochondria centric excitotoxic responses following severe penetrating traumatic brain injury |
| topic | severe traumatic brain injury time course mitochondrial damage excitotoxicity calcium homeostasis cell death |
| url | https://www.mdpi.com/2227-9059/13/7/1520 |
| work_keys_str_mv | AT hirenrmodi temporalchangesinmitochondriacentricexcitotoxicresponsesfollowingseverepenetratingtraumaticbraininjury AT sudeepmusyaju temporalchangesinmitochondriacentricexcitotoxicresponsesfollowingseverepenetratingtraumaticbraininjury AT ankehscultetus temporalchangesinmitochondriacentricexcitotoxicresponsesfollowingseverepenetratingtraumaticbraininjury AT jigneshdpandya temporalchangesinmitochondriacentricexcitotoxicresponsesfollowingseverepenetratingtraumaticbraininjury |