RESUMO
Mitochondrial permeability transition is a phenomenon in which the mitochondrial permeability transition pore (PTP) abruptly opens, resulting in mitochondrial membrane potential (ΔΨm) dissipation, loss of ATP production, and cell death. Several genetic candidates have been proposed to form the PTP complex, however, the core component is unknown. We identified a necessary and conserved role for spastic paraplegia 7 (SPG7) in Ca(2+)- and ROS-induced PTP opening using RNAi-based screening. Loss of SPG7 resulted in higher mitochondrial Ca(2+) retention, similar to cyclophilin D (CypD, PPIF) knockdown with sustained ΔΨm during both Ca(2+) and ROS stress. Biochemical analyses revealed that the PTP is a heterooligomeric complex composed of VDAC, SPG7, and CypD. Silencing or disruption of SPG7-CypD binding prevented Ca(2+)- and ROS-induced ΔΨm depolarization and cell death. This study identifies an ubiquitously expressed IMM integral protein, SPG7, as a core component of the PTP at the OMM and IMM contact site.
Assuntos
Ciclofilinas/metabolismo , Metaloendopeptidases/genética , Metaloendopeptidases/metabolismo , Mitocôndrias/metabolismo , Canal de Ânion 1 Dependente de Voltagem/metabolismo , ATPases Associadas a Diversas Atividades Celulares , Sítios de Ligação , Cálcio/metabolismo , Morte Celular , Ciclofilinas/química , Células HEK293 , Células HeLa , Humanos , Potencial da Membrana Mitocondrial , Metaloendopeptidases/química , Membranas Mitocondriais/metabolismo , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismoRESUMO
Emergency physicians rely on a multitude of different imaging modalities in the diagnosis of genitourinary emergencies. There are many considerations to be taken into account when deciding which imaging modality should be used first, as oftentimes several diagnostic tools can be used for the same pathologic condition. These factors include radiation exposure, sensitivity, specificity, age of patient, availability of resources, cost, and timeliness of completion. In this review, the strengths and weaknesses of different imaging tools in the evaluation of genitourinary emergencies are discussed.