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Published on: January 22, 2017
Targeting Cend1-Atp5f1b interaction rescues mitochondrial dysfunction and ameliorates ischemic brain injury
Hao Li1,2,3, Yi Yang4, Meng Zhang3
1Department of Neurology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China.
Abstract:
Mitochondrial dysfunction is a critical contributor to neuronal damage in acute ischemic stroke (AIS), and targeting mitochondrial function represents a promising therapeutic strategy. This study unveils the pivotal role of Cend1 protein in ischemic stroke and elucidates its underlying mechanisms. Using Cend1 knockout (KO) mice, Cend1 deficiency was shown to exacerbate cerebral ischemia/reperfusion injury, as evidenced by enlarged infarct volume, worsened neurological deficits in motor coordination and grip strength, together with alterations in mitochondrial membrane potential (ΔΨm), mPTP opening, ATP content, and the activities of respiratory Complex I and V. Mechanistically, Cend1 forms dimers via conserved GXXXA motifs in its transmembrane domain to enhance ATP synthesis. Disruption of dimerization of Cend1 (such as G130P mutation) destabilized Cend1, accelerating its degradation and abolishing ATP-enhancing effects. Atp5f1b, a mitochondrial ATP synthase subunit, was found to interact with Cend1. Furthermore, screening identified the small-molecule compound Tianeptine (TNT), which stabilizes Cend1 dimers, elevates ATP levels, and confers neuroprotection in a Cend1-dependent manner. Notably, TNT's efficacy was abolished in Cend1 KO mice, highlighting its reliance on Cend1. The findings support the Cend1/Atp5f1b interaction as a potential mitochondria-targeted mechanism, offering innovative strategies to combat ischemic stroke by enhancing bioenergetic resilience.
Insights
Cend1 protein deficiency worsens stroke outcomes by impairing mitochondrial function. The drug Tianeptine enhances Cend1 function, boosting ATP levels and offering neuroprotection in acute ischemic stroke.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Ischemic Stroke Research
Background:
- Mitochondrial dysfunction contributes significantly to neuronal damage in acute ischemic stroke (AIS).
- Targeting mitochondrial function is a promising therapeutic avenue for AIS.
- The role of Cend1 protein in ischemic stroke pathophysiology requires elucidation.
Purpose of the Study:
- To investigate the role of Cend1 protein in acute ischemic stroke.
- To elucidate the mechanisms by which Cend1 influences neuronal damage and mitochondrial function.
- To identify potential therapeutic strategies targeting Cend1 for AIS treatment.
Main Methods:
- Utilized Cend1 knockout (KO) mice to assess the impact of Cend1 deficiency on cerebral ischemia/reperfusion injury.
- Evaluated neurological deficits, infarct volume, mitochondrial membrane potential (ΔΨm), mPTP opening, ATP content, and respiratory Complex I and V activities.
- Investigated Cend1 dimerization mechanisms, its interaction with Atp5f1b, and the effect of Tianeptine (TNT) on Cend1 function and neuroprotection.
Main Results:
- Cend1 deficiency exacerbated cerebral ischemia/reperfusion injury, leading to larger infarcts and worsened neurological deficits.
- Cend1 forms dimers via GXXXA motifs to enhance ATP synthesis; mutations disrupting dimerization destabilized Cend1 and abolished its effects.
- Cend1 interacts with Atp5f1b, a mitochondrial ATP synthase subunit. Tianeptine (TNT) stabilized Cend1 dimers, increased ATP levels, and provided Cend1-dependent neuroprotection.
Conclusions:
- Cend1 plays a critical role in mitigating neuronal damage during acute ischemic stroke by maintaining mitochondrial function and ATP synthesis.
- The Cend1/Atp5f1b interaction represents a novel mitochondria-targeted mechanism for enhancing bioenergetic resilience.
- Tianeptine shows potential as a therapeutic agent for AIS by stabilizing Cend1 and improving mitochondrial ATP production.
