Necrostatin-1 mitigates mitochondrial dysfunction post-spinal cord injury

• Nec-1 alleviates the Ca2+ overload and protects the MMP in mitochondria post-SCI.
• Nec-1 increases the generation of ATP and activity of respiratory chain complex I.
• Nec-1 inhibits the release of cytochrome c and protects the mitochondrial structure.
• Nec-1 protects the mitochondrial mtDNA content, biogenesis and normal fusion, fission.
• Nec-1 could be a potential chemical to treat SCI for mitochondrial protection.

Necrostatin-1 (Nec-1) is an inhibitor of necroptosis, playing an important role in inhibition of pathological death in the central nervous system (CNS). Our earlier study suggests that Nec-1 protects the injured spinal cord. In this study, we found that Nec-1 reduces the elevated Ca2+ concentration in mitochondria post-injury and preserves the remarkably decreased mitochondrial membrane potential (MMP) level post-spinal cord injury (SCI). It also increases the generation of adenosine triphosphate (ATP) by promoting the activity of mitochondrial respiratory chain complex I instead of other complexes, which are significantly decreased due to the injury. Nec-1 also inhibits the release of cytochrome c in the mitochondria and protects the spinal cord from mitochondrial swelling post-SCI. Nec-1 promotes mitochondrial biogenesis by up-regulating mitochondrial transcription factor A (Tfam), in accordance with the mtDNA content. It also inhibits the up-regulation of mitochondrial fusion genes Mnf1, Mnf2 within 6 h post-injury and adjusts the abnormal expression of mitochondrial fission gene Fis1. All these results indicate the improvement of mitochondrial functions in injured spinal cord after the treatment of Nec-1. This research revealed the mechanisms of functional protection of Nec-1 by mitigating mitochondrial dysfunction post-SCI.