title: Sex differences in mitochondrial biogenesis determine neuronal death and survival in response to oxygen glucose deprivation and reoxygenation.
abstract: BACKGROUND
  Mitochondrial dysfunction has been linked to neuronal death and a wide array of neurodegenerative diseases. Previously, we have shown sex differences in mitochondria-mediated cell death pathways following hypoxia-ischemia. However, the role of mitochondrial biogenesis in hypoxic-ischemic brain injury between male vs. female has not been studied yet.
  
  
  RESULTS
  Primary cerebellar granule neurons (CGNs), isolated from P7 male and female mice (CD-1) segregated based on visual inspection of sex, were exposed to 2 h of oxygen glucose deprivation (OGD) followed by 6-24 h of reoxygenation (Reox). Mitochondrial membrane potential (ΔΨm) and cellular ATP levels were reduced significantly in XX CGNs as compared to XY CGNs. Mitochondrial DNA (mtDNA) content was increased (>2-fold) at 2 h OGD in XY CGNs and remained increased up to 24 h of Reox compared to XX neurons and normoxia controls. The expression of mitochondrial transcription factor A (Tfam), the nuclear respiratory factor-1 (NRF-1) and the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, were up-regulated (2-fold, ***p < 0.001) in XY CGNs but slightly reduced or remained unchanged in XX neurons. Similarly, the TFAM and PGC-1α protein levels and the mitochondrial proteins HSP60 and COXIV were increased in XY neurons only. Supportively, a balanced stimulation of fusion (Mfn 1and Mfn 2) and fission (Fis 1 and Drp 1) genes and enhanced formation of donut-shaped mitochondria were observed in XY CGNs vs. XX neurons (**p < 0.01).
  
  
  CONCLUSIONS
  Our results demonstrate that OGD/Reox alters mitochondrial biogenesis and morphological changes in a sex-specific way, influencing neuronal injury/survival differently in both sexes.
authors.forename: Jaswinder
authors.initials: J
authors.lastname: Sharma
authors.forename: Michael V
authors.initials: MV
authors.lastname: Johnston
authors.affiliation: Department of Neurology, The Hugo W, Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA. hossain@kennedykrieger.org.
authors.forename: Mir Ahamed
authors.initials: MA
authors.lastname: Hossain
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival; D005260:Female; D005947:Glucose / Q000378:metabolism*; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D063269:Mitochondrial Turnover; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism*; D012737:Sex Factors
chemical_list: D005947:Glucose; D010100:Oxygen