Mammalian Mitochondrial Complex I: Biogenesis, Regulation, and Reactive Oxygen Species Generation

Koopman, Werner J.H.; Nijtmans, Leo; Dieteren, Cindy E.; Roestenberg, Peggy; Valsecchi, Federica; Smeitink, Jan A.M.; Willems, Peter H.G.M.

doi:10.1089/ars.2009.2743

Cited by 358 publications

(328 citation statements)

References 300 publications

(419 reference statements)

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“…Fatty acids are targets for direct or indirect damage by ROS (1,(5)(6)(7)(8)16), particularly when ROS are produced by integral membrane enzymes in the respiratory chain or the photosynthetic apparatus (1,7,8,16,18). The R. sphaeroides σ E protein activates a transcriptional stress response to 1 O 2 , a ROS that is generated by integral membrane proteins of the photosynthetic apparatus (16,17,19).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and scavenging role of furan fatty acids

Lemke¹,

Peterson²,

Ziegelhoffer³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Fatty acids play important functional and protective roles in living systems. This paper reports on the synthesis of a previously unidentified 19 carbon furan-containing fatty acid, 10,13-epoxy-11-methyl-octadecadienoate (9-(3-methyl-5-pentylfuran-2-yl)nonanoic acid) (19Fu-FA), in phospholipids from Rhodobacter sphaeroides. We show that 19Fu-FA accumulation is increased in cells containing mutations that increase the transcriptional response of this bacterium to singlet oxygen ( 1 O 2 ), a reactive oxygen species generated by energy transfer from one or more light-excited donors to molecular oxygen. We identify a previously undescribed class of S-adenosylmethionine-dependent methylases that convert a phospholipid 18 carbon cis unsaturated fatty acyl chain to a 19 carbon methylated trans unsaturated fatty acyl chain (19M-UFA). We also identify genes required for the O 2 -dependent conversion of this 19M-UFA to 19Fu-FA. Finally, we show that the presence of 1 O 2 leads to turnover of 19Fu-Fa in vivo. We propose that furan-containing fatty acids like 19Fu-FA can act as a membrane-bound scavenger of 1 O 2 , which is naturally produced by integral membrane enzymes of the R. sphaeroides photosynthetic apparatus.radical scavenger | oxygenated fatty acid | fatty acyl methylase

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Section: Resultsmentioning

confidence: 99%

Synthesis and scavenging role of furan fatty acids

Lemke¹,

Peterson²,

Ziegelhoffer³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The inhibition of Complex I as a JNK-mediated event is an interesting observation, as tyrosine phosphorylation is thought to be the primary post-translational mechanism for controlling respiratory complex activity (44,45). Complex I is a 45-subunit protein complex that resides in the inner mitochondrial membrane with projections into the mitochondria inner/outer membrane space and the mitochondrial matrix (45).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial c-Jun N-terminal Kinase (JNK) Signaling Initiates Physiological Changes Resulting in Amplification of Reactive Oxygen Species Generation

Chambers

LoGrasso

2011

Journal of Biological Chemistry

169

159

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The JNK signaling cascade is critical for cellular responses to a variety of environmental and cellular stimuli. Although gene expression aspects of JNK signal transduction are well studied, there are minimal data on the physiological impact of JNK signaling. To bridge this gap, we investigated how JNK impacted physiology in HeLa cells. We observed that inhibition of JNK activity and JNK silencing with siRNA reduced the level of reactive oxygen species (ROS) generated during anisomycin-induced stress in HeLa cells. Silencing p38 had no significant impact on ROS generation under anisomycin stress. Moreover, JNK signaling mediated amplification of ROS production during stress. Mitochondrial superoxide production was shown to be the source of JNK-induced ROS amplification, as an NADPH oxidase inhibitor demonstrated little impact on JNK-mediated ROS generation. Using mitochondrial isolation from JNK null fibroblasts and targeting the mitochondrial scaffold of JNK, Sab, we demonstrated that mitochondrial JNK signaling was responsible for mitochondrial superoxide amplification. These results suggest that cellular stress altered mitochondria, causing JNK to translocate to the mitochondria and amplify up to 80% of the ROS generated largely by Complex I. This work demonstrates that a sequence of events exist for JNK mitochondrial signaling whereby ROS activates JNK, thereby affecting mitochondrial physiology, which can have effects on cell survival and death.

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“…S4C). Mitochondria are regarded as the major source of cellular ROS (18). Recent studies have reported that mROS promotes NLRP3 activation (19).…”

Section: Pai-2 Mediates Loss Of Mitochondrial Integrity and A Decreasmentioning

confidence: 99%

TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation

Chuang

Yang

Chou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

136

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The NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, a multiprotein complex, triggers caspase-1 activation and maturation of the proinflammatory cytokines IL-1β and IL-18 upon sensing a wide range of pathogen-and damage-associated molecules. Dysregulation of NLRP3 inflammasome activity contributes to the pathogenesis of many diseases, but its regulation remains poorly defined. Here we show that depletion of plasminogen activator inhibitor type 2 (PAI-2), a serine protease inhibitor, resulted in NLRP3-and ASC (apoptosis-associated Specklike protein containing a C-terminal caspase recruitment domain)-dependent caspase-1 activation and IL-1β secretion in macrophages upon Toll-like receptor 2 (TLR2) and TLR4 engagement. TLR2 or TLR4 agonist induced PAI-2 expression, which subsequently stabilized the autophagic protein Beclin 1 to promote autophagy, resulting in decreases in mitochondrial reactive oxygen species, NLRP3 protein level, and pro-IL-1β processing. Likewise, overexpressing Beclin 1 in PAI-2-deficient cells rescued the suppression of NLRP3 activation in response to LPS. Together, our data identify a tier of TLR signaling in controlling NLRP3 inflammasome activation and reveal a cell-autonomous mechanism which inversely regulates TLR-or Escherichia coli-induced mitochondrial dysfunction, oxidative stress, and IL-1β-driven inflammation.

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Mammalian Mitochondrial Complex I: Biogenesis, Regulation, and Reactive Oxygen Species Generation

Cited by 358 publications

References 300 publications

Synthesis and scavenging role of furan fatty acids

Synthesis and scavenging role of furan fatty acids

Mitochondrial c-Jun N-terminal Kinase (JNK) Signaling Initiates Physiological Changes Resulting in Amplification of Reactive Oxygen Species Generation

TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation

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