Mitochondria as multifaceted regulators of cell death - 2019 nature review
작성자문형철작성시간22.10.21조회수241 목록 댓글 0
Through their many and varied metabolic functions, mitochondria power life. Paradoxically, mitochondria also have a central role in apoptotic cell death. Upon induction of mitochondrial apoptosis, mitochondrial outer membrane permeabilization (MOMP) usually commits a cell to die. Apoptotic signalling downstream of MOMP involves cytochrome c release from mitochondria and subsequent caspase activation. As such, targeting MOMP in order to manipulate cell death holds tremendous therapeutic potential across different diseases, including neurodegenerative diseases, autoimmune disorders and cancer.
그들의 많고 다양한 대사 기능을 통해 미토콘드리아는 생명에 힘을 실어줍니다. 역설적이게도, 미토콘드리아는 또한 세포자멸사 세포사에 중심적인 역할을 합니다. 미토콘드리아 세포자멸사 유도 시, 미토콘드리아 외막 투과화(MOMP)는 일반적으로 세포를 죽게 만듭니다. MOMP의 아폽토시스 신호 하류는 미토콘드리아에서 시토크롬 c 방출 및 후속 카스파제 활성화를 포함합니다. 이와 같이 세포 사멸을 조작하기 위해 MOMP를 표적으로 하는 것은 신경퇴행성 질환, 자가면역 장애 및 암을 비롯한 다양한 질병에 걸쳐 엄청난 치료 잠재력을 보유합니다.
In this Review, we discuss new insights into how mitochondria regulate apoptotic cell death. Surprisingly, recent data demonstrate that besides eliciting caspase activation, MOMP engages various pro-inflammatory signalling functions. As we highlight, together with new findings demonstrating cell survival following MOMP, this pro-inflammatory role suggests that mitochondria-derived signalling downstream of pro-apoptotic cues may also have non-lethal functions.
이 리뷰에서 우리는 미토콘드리아가 세포 사멸을 조절하는 방법에 대한 새로운 통찰력을 논의합니다. 놀랍게도, 최근 데이터는 카스파제 활성화를 유도하는 것 외에도 MOMP가 다양한 전-염증성 신호 전달 기능에 관여한다는 것을 보여줍니다. 우리가 강조하는 바와 같이, MOMP 후 세포 생존을 입증하는 새로운 발견과 함께, 이 염증 촉진 역할은 pro-apoptotic 신호의 하류에서 미토콘드리아 유래 신호 전달이 치명적이지 않은 기능을 가질 수 있음을 시사합니다.
Finally, we discuss the importance and roles of mitochondria in other forms of regulated cell death, including necroptosis, ferroptosis and pyroptosis. Collectively, these new findings offer exciting, unexplored opportunities to target mitochondrial regulation of cell death for clinical benefit.
마지막으로 necroptosis, ferroptosis 및 pyroptosis를 포함하여 조절된 세포 사멸의 다른 형태에서 미토콘드리아의 중요성과 역할에 대해 논의합니다. 종합적으로, 이러한 새로운 발견은 임상적 이점을 위해 세포 사멸의 미토콘드리아 조절을 표적으로 하는 흥미롭고 미개척된 기회를 제공합니다.
Pro-inflammatory effects of mitochondrial outer membrane permeabilization. Mitochondrial outer membrane permeabilization (MOMP) can induce inflammation in multiple ways. Following MOMP, the outer membrane pores progressively widen, enabling inner mitochondrial membrane (IMM) extrusion and rupture (step 1). This allows mitochondrial DNA (mtDNA) release into the cytosol whereupon it can engage cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signalling, leading to pro-inflammatory interferon signalling. MOMP causes the proteasomal degradation of inhibitors of apoptosis proteins (IAPs), which leads to upregulation of nuclear factor-κB-inducing kinase (NIK) causing pro-inflammatory nuclear factor-κB (NF-κB) signalling and activation of caspase 8, in turn causing maturation of proinflammatory IL-1β (step 2). Under conditions of defective degradation of mitochondrial double-stranded RNA (dsRNA), such as knockdown of RNA degradosome components, dsRNA is released via an ill-defined mechanism from the mitochondria in a BAX/BAK-dependent manner (step 3). In the cytosol, dsRNA can bind adaptor protein MDA5, which then binds mitochondrial antiviral signalling protein (MAVS), which subsequently oligomerizes and activates NF-κB and interferon regulatory factor 3 (IRF3) to induce an interferon response. cGAMP, cyclic guanosine monophosphate–adenosine monophosphate; TBK1, TANK binding kinase 1.
inhibition of mitochondrial outer membrane permeabilization-induced inflammation. Inflammatory signalling downstream of mitochondrial outer membrane permeabilization (MOMP) is regulated in multiple ways.
First, caspases inhibit multiple processes required for pro-inflammatory cytokine synthesis and secretion. This includes general downregulation of protein translation and canonical protein secretion to prevent the production and release of inflammatory cytokines. Caspases also directly cleave and inactivate various pro-inflammatory signalling molecules including cyclic GMP–AMP synthase (cGAS), mitochondrial antiviral signalling protein (MAVS) and interferon regulatory factor 3 (IRF3). Caspase activity also promotes the quick death and phagocytic removal of dying cells by invoking ‘find-me’ and ‘eat-me’ signals, limiting the time in which the dying cells can produce pro-inflammatory signalling molecules. Beyond the role of caspases, MOMP is associated with the release of RNA degradasome component polyribonucleotide nucleotidyl transferase 1 (PNPT1), which can cause global mRNA degradation, likely causing downregulation of inflammatory gene transcripts. MOMP also activates autophagy, which sequesters permeabilized mitochondria and inhibits the release of pro-inflammatory IFNβ.
Strategies to target mitochondrial apoptosis in disease. Apoptosis can be activated either through inhibition of anti-apoptotic B cell lymphoma 2 (BCL-2) proteins (with BH3-mimetics) or by directly activating BAX/BAK (for example, with small molecules) (step 1). Such approaches have a proven use in oncology and have a clinical potential in the treatment of autoimmunity, fibrosis and ageing. Efficient inhibition of mitochondrial apoptosis can be achieved via blocking BAX and BAK (for example, with small molecules), which has a potential use in counteracting pathological cell loss, for instance, in the context of neurodegenerative diseases or infection (step 2). Inhibition of caspase function following mitochondrial outer membrane permeabilization (MOMP; see also Fig. 3) has the potential to turn apoptosis into an immunogenic type of cell death, which could be used to boost immune responses in antitumour and antiviral therapies (step 3). Better understanding of the heterogeneity of MOMP and mechanisms of mitochondrial network recovery in the absence of cell death following MOMP could be used to promote cell survival in the context of cell loss in response to various insults, such as stroke or infarction (step 4).