Reactive oxygen species generation by reverse electron transfer at mitochondrial complex I under simulated early reperfusion conditions
Ischemic tissues accumulate succinate, which is rapidly oxidized upon reperfusion, driving a burst of mitochondrial reactive oxygen species (ROS) generation that triggers cell death. In isolated mitochondria with succinate as the sole metabolic substrate under non-phosphorylating conditions, 90 % of...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-04-01
|
| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231724000235 |
| _version_ | 1797300378402816000 |
|---|---|
| author | Caio Tabata Fukushima Ian-Shika Dancil Hannah Clary Nidhi Shah Sergiy M. Nadtochiy Paul S. Brookes |
| author_facet | Caio Tabata Fukushima Ian-Shika Dancil Hannah Clary Nidhi Shah Sergiy M. Nadtochiy Paul S. Brookes |
| author_sort | Caio Tabata Fukushima |
| collection | DOAJ |
| description | Ischemic tissues accumulate succinate, which is rapidly oxidized upon reperfusion, driving a burst of mitochondrial reactive oxygen species (ROS) generation that triggers cell death. In isolated mitochondria with succinate as the sole metabolic substrate under non-phosphorylating conditions, 90 % of ROS generation is from reverse electron transfer (RET) at the Q site of respiratory complex I (Cx-I). Together, these observations suggest Cx-I RET is the source of pathologic ROS in reperfusion injury. However, numerous factors present in early reperfusion may impact Cx-I RET, including: (i) High [NADH]; (ii) High [lactate]; (iii) Mildly acidic pH; (iv) Defined ATP/ADP ratios; (v) Presence of the nucleosides adenosine and inosine; and (vi) Defined free [Ca2+]. Herein, experiments with mouse cardiac mitochondria revealed that under simulated early reperfusion conditions including these factors, total mitochondrial ROS generation was only 56 ± 17 % of that seen with succinate alone (mean ± 95 % confidence intervals). Of this ROS, only 52 ± 20 % was assignable to Cx-I RET. A further 14 ± 7 % could be assigned to complex III, with the remainder (34 ± 11 %) likely originating from other ROS sources upstream of the Cx-I Q site. Together, these data suggest the relative contribution of Cx-I RET ROS to reperfusion injury may be overestimated, and other ROS sources may contribute a significant fraction of ROS in early reperfusion. |
| first_indexed | 2024-03-07T23:06:20Z |
| format | Article |
| id | doaj.art-a660219d5cd04eae9638469880173663 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-03-07T23:06:20Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-a660219d5cd04eae96384698801736632024-02-22T04:52:16ZengElsevierRedox Biology2213-23172024-04-0170103047Reactive oxygen species generation by reverse electron transfer at mitochondrial complex I under simulated early reperfusion conditionsCaio Tabata Fukushima0Ian-Shika Dancil1Hannah Clary2Nidhi Shah3Sergiy M. Nadtochiy4Paul S. Brookes5Departments of Anesthesiology, University of Rochester Medical Center, USA; Departments of Biochemistry, University of Rochester Medical Center, USA; Pharmacology and Physiology, University of Rochester Medical Center, USADepartments of Anesthesiology, University of Rochester Medical Center, USADepartments of Biochemistry, University of Rochester Medical Center, USAPharmacology and Physiology, University of Rochester Medical Center, USADepartments of Anesthesiology, University of Rochester Medical Center, USADepartments of Anesthesiology, University of Rochester Medical Center, USA; Pharmacology and Physiology, University of Rochester Medical Center, USA; Corresponding author. Department of Anesthesiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.Ischemic tissues accumulate succinate, which is rapidly oxidized upon reperfusion, driving a burst of mitochondrial reactive oxygen species (ROS) generation that triggers cell death. In isolated mitochondria with succinate as the sole metabolic substrate under non-phosphorylating conditions, 90 % of ROS generation is from reverse electron transfer (RET) at the Q site of respiratory complex I (Cx-I). Together, these observations suggest Cx-I RET is the source of pathologic ROS in reperfusion injury. However, numerous factors present in early reperfusion may impact Cx-I RET, including: (i) High [NADH]; (ii) High [lactate]; (iii) Mildly acidic pH; (iv) Defined ATP/ADP ratios; (v) Presence of the nucleosides adenosine and inosine; and (vi) Defined free [Ca2+]. Herein, experiments with mouse cardiac mitochondria revealed that under simulated early reperfusion conditions including these factors, total mitochondrial ROS generation was only 56 ± 17 % of that seen with succinate alone (mean ± 95 % confidence intervals). Of this ROS, only 52 ± 20 % was assignable to Cx-I RET. A further 14 ± 7 % could be assigned to complex III, with the remainder (34 ± 11 %) likely originating from other ROS sources upstream of the Cx-I Q site. Together, these data suggest the relative contribution of Cx-I RET ROS to reperfusion injury may be overestimated, and other ROS sources may contribute a significant fraction of ROS in early reperfusion.http://www.sciencedirect.com/science/article/pii/S2213231724000235MitochondriaIschemiaReperfusionComplex-IReverse electron transferReactive oxygen species |
| spellingShingle | Caio Tabata Fukushima Ian-Shika Dancil Hannah Clary Nidhi Shah Sergiy M. Nadtochiy Paul S. Brookes Reactive oxygen species generation by reverse electron transfer at mitochondrial complex I under simulated early reperfusion conditions Redox Biology Mitochondria Ischemia Reperfusion Complex-I Reverse electron transfer Reactive oxygen species |
| title | Reactive oxygen species generation by reverse electron transfer at mitochondrial complex I under simulated early reperfusion conditions |
| title_full | Reactive oxygen species generation by reverse electron transfer at mitochondrial complex I under simulated early reperfusion conditions |
| title_fullStr | Reactive oxygen species generation by reverse electron transfer at mitochondrial complex I under simulated early reperfusion conditions |
| title_full_unstemmed | Reactive oxygen species generation by reverse electron transfer at mitochondrial complex I under simulated early reperfusion conditions |
| title_short | Reactive oxygen species generation by reverse electron transfer at mitochondrial complex I under simulated early reperfusion conditions |
| title_sort | reactive oxygen species generation by reverse electron transfer at mitochondrial complex i under simulated early reperfusion conditions |
| topic | Mitochondria Ischemia Reperfusion Complex-I Reverse electron transfer Reactive oxygen species |
| url | http://www.sciencedirect.com/science/article/pii/S2213231724000235 |
| work_keys_str_mv | AT caiotabatafukushima reactiveoxygenspeciesgenerationbyreverseelectrontransferatmitochondrialcomplexiundersimulatedearlyreperfusionconditions AT ianshikadancil reactiveoxygenspeciesgenerationbyreverseelectrontransferatmitochondrialcomplexiundersimulatedearlyreperfusionconditions AT hannahclary reactiveoxygenspeciesgenerationbyreverseelectrontransferatmitochondrialcomplexiundersimulatedearlyreperfusionconditions AT nidhishah reactiveoxygenspeciesgenerationbyreverseelectrontransferatmitochondrialcomplexiundersimulatedearlyreperfusionconditions AT sergiymnadtochiy reactiveoxygenspeciesgenerationbyreverseelectrontransferatmitochondrialcomplexiundersimulatedearlyreperfusionconditions AT paulsbrookes reactiveoxygenspeciesgenerationbyreverseelectrontransferatmitochondrialcomplexiundersimulatedearlyreperfusionconditions |