Mitochondrial dynamics and sex-specific responses in the developing rat hippocampus: Effect of perinatal asphyxia and mesenchymal stem cell Secretome treatment

Abstract

Aims

Perinatal asphyxia is one of the major causes of neonatal death at birth. Survivors can progress but often suffer from long-term sequelae. We aim to determine the effects of perinatal asphyxia on mitochondrial dynamics and whether mesenchymal stem cell secretome (MSC-S) treatment can alleviate the deleterious effects.

Materials and methods

Animals were subjected to 21 min of asphyxia at the time of delivery. MSC-S or vehicle was intranasally administered 2 h post-delivery. Mitochondrial mass (D-loop, qPCR), mitochondrial dynamics proteins (Drp1, Fis1 and OPA1, Western blot), mitochondrial dynamics (TOMM20, Immunofluorescence), as well as mitochondrial membrane potential (ΔΨ_m) (Safranin O) were evaluated at P1 and P7 in the hippocampus.

Key findings

Perinatal asphyxia increased levels of mitochondrial dynamics proteins Drp1 and S-OPA1 at P1 and Fis1 at P7. Mitochondrial density and mass were decreased at P1. Perinatal asphyxia induced sex-specific differences, with increased L-OPA1 in females at P7 and increased mitochondria circularity. In males, asphyxia-exposed animals exhibited a reduced ΔΨ_m at P7. MSC-S treatment normalised levels of mitochondrial dynamics proteins involved in fission.

Significance

This study provides novel insights into the effects of perinatal asphyxia on mitochondrial dynamics in the developing brain and on the therapeutic opportunities provided by mesenchymal stem cell secretome treatment. It also highlights on the relevance of considering sex as a biological variable in perinatal brain injury and therapy development. These findings contribute to the development of targeted, personalised therapies for infants affected by perinatal asphyxia.