Induction of Mitochondrial Fragmentation and Mitophagy after Neonatal Hypoxia–Ischemia

Nair, Syam; Leverin, Anna-Lena; Rocha-Ferreira, Eridan; Sobotka, Kristina; Thornton, Claire; Mallard, Carina; Hagberg, Henrik

Abstract

Abstract: Hypoxia–ischemia (HI) leads to immature brain injury mediated by mitochondrial stress.
If damaged mitochondria cannot be repaired, mitochondrial permeabilization ensues, leading to cell
death. Non-optimal turnover of mitochondria is critical as it affects short and long term structural
and functional recovery and brain development. Therefore, disposal of deficient mitochondria via
mitophagy and their replacement through biogenesis is needed. We utilized mt-Keima reporter
mice to quantify mitochondrial morphology (fission, fusion) and mitophagy and their mechanisms
in primary neurons after Oxygen Glucose Deprivation (OGD) and in brain sections after neonatal
HI. Molecular mechanisms of PARK2-dependent and -independent pathways of mitophagy were
investigated in vivo by PCR andWestern blotting. Mitochondrial morphology and mitophagy were
investigated using live cell microscopy. In primary neurons, we found a primary fission wave
immediately after OGD with a significant increase in mitophagy followed by a secondary phase of
fission at 24 h following recovery. Following HI, mitophagy was upregulated immediately after HI
followed by a second wave at 7 days. Western blotting suggests that both PINK1/Parkin-dependent
and -independent mechanisms, including NIX and FUNDC1, were upregulated immediately after HI,
whereas a PINK1/Parkin mechanism predominated 7 days after HI.We hypothesize that excessive
mitophagy in the early phase is a pathologic response which may contribute to secondary energy
depletion, whereas secondary mitophagy may be involved in post-HI regeneration and repair.

Citation

Nair, S., Leverin, A., Rocha-Ferreira, E., Sobotka, K., Thornton, C., Mallard, C., & Hagberg, H. (2022). Induction of Mitochondrial Fragmentation and Mitophagy after Neonatal Hypoxia–Ischemia. Cells, https://doi.org/10.3390/cells11071193

• Journal Article Type: Article
• Acceptance Date: Mar 30, 2022
• Publication Date: Apr 1, 2022
• Deposit Date: Jul 15, 2022
• Publicly Available Date: Jul 18, 2022
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.3390/cells11071193