Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Effects of Transient Treatment with Rotenone, a Mitochondrial Inhibitor, on Mouse Subventricular Zone Neural Stem Cells

미토콘드리아 저해제인 rotenone의 일시적 처리가 쥐의 뇌실 하 영역 신경 줄기 세포에 미치는 영향

  • 박기엽 (KAIST 부설 한국과학영재학교) ;
  • 김만수 (인제대학교 약학대학)
  • Received : 2019.11.20
  • Accepted : 2019.12.11
  • Published : 2019.12.30
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Abstract

Subventricular zone (SVZ) in the brain contains neural stem cells (NSCs) which self-renew and differentiate to neurons and glial cells during postnatal period and throughout adulthood. Since fate decision to either proliferation or differentiation has to respond to intracellular and extracellular conditions, many intrinsic and extrinsic factors are involved. Among them, mitochondria have been reported to participate in fate decision of NSCs. In our previous report, we showed that long-term treatment of a mitochondrial inhibitor rotenone greatly inhibited neurogenesis. In this study, we examined the effects of short-term treatment of rotenone on SVZ NSCs. We found that (1) even one-day treatment of rotenone significantly reduced neurogenesis and earlier time points seemed to be more sensitive to rotenone, (2) a number of Mash1+ transit amplifying cells was decreased by one-day treatment of rotenone, (3) short-term treatment of rotenone eliminated most of the differentiated Tuj1+ neurons and Olig2+ oligodendrocytes, while glial fibrillary acidic protein (GFAP)+ astrocytes were not affected, and (4) sulfiredoxin 1 (Srxn1) gene expression was increased after one-day treatment of rotenone, indicating activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. All these results confirm that functional mitochondria are necessary during differentiation to neurons or oligodendrocytes as well as maintenance of neurons after differentiation. Also, these data suggest that temporary exposure to mitochondrial inhibitor such as rotenone might have long-term effects on neurogenic potential of NSCs.

뇌에서 뇌실하 영역은 자가 복제 및 신경세포와 교세포로 분화하는 신경줄기세포가 위치한 곳이다. 이러한 신경줄기세포는 태어난 직후 뿐만 아니라, 성인기까지 존재한다. 세포 증식과 분화에 대한 결정은 세포 안과 밖의 상황에 따라 조절될 필요가 있기에, 많은 세포 내부 또는 세포 외부의 인자들이 이러한 결정에 관여한다. 이러한 인자들 중에서 미토콘드리아는 신경줄기세포의 운명 결정에 관여함이 보고된 바 있다. 본 저자들의 이전 논문에서, 미토콘드리아 저해제인 rotenone을 장시간 처리했을 때, 신경세포로의 분화가 거의 일어나지 않았음을 보여주었다. 이번 연구에서, rotenone을 뇌실하 영역 신경줄기세포에 단기간 처리했을 때의 영향에 대해 조사하였다. 이를 통해 다음과 같은 결과를 관찰하였다. (1) 하루 동안 rotenone을 처리하자 신경세포로의 분화가 크게 감소하였고, 특히 분화 초기 단계가 더 민감하게 억제되었다. (2) 일시적 증식세포인 Mash1+ 세포의 수가 rotenone을 하루 처리한 후 감소하였다. (3) 분화가 된 Tuj1+ 신경세포와 Olig2+ 희소 돌기 아교 세포 (oligodendrocytes) 모두 rotenone을 단기간 처리하자 감소하였다. 반면, glial fibrillary acidic protein (GFAP)+성상 세포 (astrocytes)의 수는 변화하지 않았다. (4) sulfiredoxin 1 (Srxn1) 유전자 발현이 rotenone을 하루 처리한 후 증가하였는데, 이는 nuclear factor (erythroid-derived 2)-like 2 (Nrf2) 신호전달 경로가 활성화 되었음을 말해준다. 이러한 실험 결과는 기능을 갖춘 미토콘드리아가 신경세포 또는 희소 돌기 아교 세포로의 분화 뿐 아니라, 이미 분화가 끝난 신경세포의 유지에도 필요함을 확인해 주었다. 또한, 이러한 결과는 rotenone과 같은 미토콘드리아의 저해제에 짧은 시간 노출 되더라도 신경줄기세포의 신경세포로의 분화 가능성에 장기적인 영향을 미칠 수 있음을 시사한다.

Keywords

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