This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/5846440. The authors presented an interesting work to understand the role of mitochondria in multiple sclerosis (MS) progression. The current therapeutic strategy largely focuses on the management of immune response there is an unmet need for better understanding progression and developing novel strategies to slow down disease progression. The authors took a methodical approach and demonstrated that by reviving mitochondrial activity by overexpressing Pgc-1α in an experimental autoimmune encephalomyelitis mice model (EAE) they were able to rescue the EAE mice better than the WT mice. For their EAE mouse model, the authors used C57Bl mice immunized with myelin oligodendrocyte glycoprotein 35–55 peptide. Even though this model was widely used to understand multiple sclerosis, it is understood that the model is monophasic i.e. there is no clinical progression of disease after onset as presented in humans. It would be interesting to see how other EAE models such as Biozzi ABH mice respond to Pgc-1α overexpression especially on the relapsing episodes. The cuprizone model is another interesting model where mitochondrial density increase was similar to post mortem MS pathophysiology. The authors did show induction of Pgc-1α increased calcium clearance, but they did not study the effect on ATP production. It will be informative if they can compare ATP levels in Pgc-1α induced and wild-type cells.