Mitochondrial Optic Atrophy (OPA) 1 Processing Is Altered in Response to Neonatal Hypoxic-Ischemic Brain Injury

Baburamani, Ana A.; Hurling, Chloe; Stolp, Helen B.; Sobotka, Kristina; Gressèns, Pierre; Hagberg, Henrik; Thornton, Claire

doi:10.3390/ijms160922509

Cited by 50 publications

(49 citation statements)

References 52 publications

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“…Oxidative insults that deplete ATP and damage the mitochondrial membrane such as H 2 O 2 also induce degradation of YME1L, but not activated OMA1 (Rainbolt et al, 2015). Similarly, YME1L is destabilized, while OMA1 remains stable, in mice subjected to hypoxic-ischemic (HI) injury, a pathologic condition that depletes cellular ATP and induces mitochondrial dysfunction (Baburamani et al, 2015). …”

Section: Resultsmentioning

confidence: 99%

“…4E,F). OMA1 and YME1L protein levels also return to normal levels in vivo following recovery from acute HI injury (Baburamani et al, 2015). Apart from OMA1 degradation, other factors could also influence OMA1-dependent OPA1 processing during recovery from CCCP + 2-DG pretreatment such as reductions in OMA1 protease activity afforded by restoration of the membrane potential, slowed OPA1 biosynthesis (Frezza et al, 2006; Patten et al, 2014), or posttranslational modifications of OMA1 and/or OPA1 (Samant et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

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Reciprocal Degradation of YME1L and OMA1 Adapts Mitochondrial Proteolytic Activity during Stress

et al. 2016

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SUMMARY The mitochondrial inner membrane proteases YME1L and OMA1 are critical regulators of essential mitochondrial functions including inner membrane proteostasis maintenance and mitochondrial dynamics. Here, we show that YME1L and OMA1 are reciprocally degraded in response to distinct types of cellular stress. OMA1 is degraded through a YME1L-dependent mechanism in response to toxic insults that depolarize the mitochondrial membrane. Alternatively, insults that depolarize mitochondria and deplete cellular ATP stabilize active OMA1 and promote YME1L degradation. We show that the differential degradation of YME1L and OMA1 alters their proteolytic processing of the dynamin-like GTPase OPA1, a critical regulator of mitochondrial inner membrane morphology, which influences the recovery of tubular mitochondria following membrane depolarization-induced fragmentation. Our results reveal the differential stress-induced degradation of YME1L and OMA1 as a mechanism to sensitively adapt mitochondrial inner membrane protease activity and function in response to distinct types of cellular insults.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Reciprocal Degradation of YME1L and OMA1 Adapts Mitochondrial Proteolytic Activity during Stress

et al. 2016

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“…Fission occurs as an early event in a number of neurodegenerative diseases including Alzheimer's disease [26] and Huntington's disease [27] as well as occurring after brain trauma such as stroke or neonatal hypoxic-ischaemic injury [28,29], environments in which AMPK is known to be activated [30][31][32]. Indeed, inhibitors of post-injury fission, such as mDivi-1 and p110, have proved successful as neuroprotectants.…”

Section: Figure 1 Mitochondrial Dynamicsmentioning

confidence: 99%

AMPK: keeping the (power)house in order?

Thornton

2017

Neuronal Signaling

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Metabolically energetic organs, such as the brain, require a reliable source of ATP, the majority of which is provided by oxidative phosphorylation in the mitochondrial matrix. Maintaining mitochondrial integrity is therefore of paramount importance in highly specialized cells such as neurons. Beyond acting as cellular 'power stations' and initiators of apoptosis, neuronal mitochondria are highly mobile, transported to pre-and post-synaptic sites for rapid, localized ATP production, serve to buffer physiological and pathological calcium and contribute to dendritic arborization. Given such roles, it is perhaps unsurprising that recent studies implicate AMP-activated protein kinase (AMPK), a cellular energy-sensitive metabolic regulator, in triggering mitochondrial fission, potentially balancing mitochondrial dynamics, biogenesis and mitophagy.Although the brain constitutes approximately only 2% of our total body weight, it accounts for the usage of in excess of 20% of our oxygen intake and is one of the most metabolically active tissues in our bodies. Approximately 90% ATP production occurs through oxidative phosphorylation in mitochondria, therefore, for tissues with a high metabolic rate such as the brain, regulating mitochondrial health is key to sustaining cellular function [1].Mitochondria are dynamic, double-membraned organelles that continually undergo fission, fusion and quality control (mitophagy) [2]. Long-term failure of either fission or fusion can lead to deleterious consequences and thus, a balance of these processes together with mitophagy is critical to maintaining cellular homoeostasis. Over the last 20 years, there has been a flurry of interest in discerning the molecular mechanisms regulating this mitochondrial life cycle, with significant success. Inner and outer mitochondrial membrane fusion are governed by optic atrophy (OPA)1 and mitofusin1/2 respectively whereas fission is mediated by the cytosolic protein, dynamin-related protein (Drp)1 (Figure 1) [3]. Drp1 is recruited to the mitochondrial outer membrane by binding to one of a number of mitochondrially located adaptors such as mitochondrial fission factor (Mff) and mitochondrial fission protein (Fis)1, mitochondrial dynamics proteins of 49 and 51 kDa (MiD49/51) [2,4]. Mitophagy plays a key role in the life cycle of the mitochondrion. Not only does it ensure that damaged mitochondria are neutralized, but physiological mitophagy can also regulate the number of mitochondria and their turnover [5]. In response to the decorating of the outer membrane of a depolarized mitochondrion with ubiquitin, an isolation membrane is recruited to extend round and engulf the mitochondrion, subsequently fusing with a lysosome to acidify and recycle the contents (Figure 1). Fission is frequently observed as a prelude to mitophagy as well as in the initiation of apoptosis [6]. Fusion generates a mitochondrial reticulum, allowing mitochondrial contents to mix, preventing the accumulation of mitochondrial DNA mutations as well as promoting enhanced ATP synthesi...

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“…The Optic Atrophy 1 (OPA1) mitochondrial inner membrane protein is necessary for maintaining normal cristae structure and cytochrome c localization (Frezza et al, 2006). The fact that OPA1 is proteolytically degraded in a rat model of cerebral ischemia reperfusion could also help explain why Ca 2+ -induced cytochrome c release is high in mitochondria 24 h after cardiac arrest and resuscitation (Baburamani et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Calcium uptake and cytochrome c release from normal and ischemic brain mitochondria

Andreyev

Tamrakar

Rosenthal

et al. 2018

Neurochemistry International

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At abnormally elevated levels of intracellular Ca2+, mitochondrial Ca2+ uptake may compromise mitochondrial electron transport activities and trigger membrane permeability changes that allow for release of cytochrome c and other mitochondrial apoptotic proteins into the cytosol. In this study, a clinically relevant canine cardiac arrest model was used to assess the effects of global cerebral ischemia and reperfusion on mitochondrial Ca2+ uptake capacity, Ca2+ uptake-mediated inhibition of respiration, and Ca2+-induced cytochrome c release, as measured in vitro in a K+-based medium in the presence of Mg2+, ATP, and NADH-linked oxidizable substrates. Maximum Ca2+ uptake by frontal cortex mitochondria was significantly lower following 10 min cardiac arrest compared to non-ischemic controls. Mitochondria from ischemic brains were also more sensitive to the respiratory inhibition associated with accumulation of large levels of Ca2+. Cytochrome c was released from brain mitochondria in vitro in a Ca2+-dose-dependent manner and was more pronounced following both 10 min of ischemia alone and following 24 h reperfusion, in comparison to mitochondria from non-ischemic Shams. These effects of ischemia and reperfusion on brain mitochondria could compromise intracellular Ca2+ homeostasis, decrease aerobic and increase anaerobic cerebral energy metabolism, and potentiate the cytochrome c-dependent induction of apoptosis, when re-oxygenated mitochondria are exposed to abnormally high levels of intracellular Ca2+.

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Mitochondrial Optic Atrophy (OPA) 1 Processing Is Altered in Response to Neonatal Hypoxic-Ischemic Brain Injury

Cited by 50 publications

References 52 publications

Reciprocal Degradation of YME1L and OMA1 Adapts Mitochondrial Proteolytic Activity during Stress

Reciprocal Degradation of YME1L and OMA1 Adapts Mitochondrial Proteolytic Activity during Stress

AMPK: keeping the (power)house in order?

Calcium uptake and cytochrome c release from normal and ischemic brain mitochondria

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