Multiple pathways for sorting mitochondrial precursor proteins

Bolender, Natalia; Sickmann, Albert; Wagner, Richard; Meisinger, Chris; Pfanner, Nikolaus

doi:10.1038/sj.embor.7401126

Cited by 289 publications

(263 citation statements)

References 52 publications

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“…However, TDP1 has similar size both in the nuclear and mitochondrial fractions ( Fig. 2A) and does not contain a MTS sequence (10,60). This implies that TDP1, like many other proteins and transcription factors such as APE1, FEN1, NF-kB, p53, and BRCA1 (23) that act both in the nucleus and mitochondria, enter mitochondria despite their lack of canonical mitochondria targeting sequences, indicating the existence of still unknown mechanisms of intracellular trafficking (13,14,28,61,62).…”

Section: Discussionmentioning

confidence: 99%

Role of tyrosyl-DNA phosphodiesterase (TDP1) in mitochondria

Das

Dexheimer

Maddali

et al. 2010

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

130

152

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Human tyrosyl-DNA phosphodiesterase (TDP1) hydrolyzes the phosphodiester bond at a DNA 3′-end linked to a tyrosyl moiety and has been implicated in the repair of topoisomerase I (Top1)-DNA covalent complexes. TDP1 can also hydrolyze other 3′-end DNA alterations including 3′-phosphoglycolate and 3′-abasic sites, and exhibits 3′-nucleosidase activity indicating it may function as a general 3′-end-processing DNA repair enzyme. Here, using laser confocal microscopy, subcellular fractionation and biochemical analyses we demonstrate that a fraction of the TDP1 encoded by the nuclear TDP1 gene localizes to mitochondria. We also show that mitochondrial base excision repair depends on TDP1 activity and provide evidence that TDP1 is required for efficient repair of oxidative damage in mitochondrial DNA. Together, our findings provide evidence for TDP1 as a novel mitochondrial enzyme.DNA repair | ligase III | oxidative DNA damage | topoisomerase I | mitochondrial BER

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Section: Discussionmentioning

confidence: 99%

Role of tyrosyl-DNA phosphodiesterase (TDP1) in mitochondria

Das

Dexheimer

Maddali

et al. 2010

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

130

152

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“…The classic mitochondrial targeting sequence is an N-terminal motif that forms an amphipathic helix with a high proportion of positively charged basic residues (20,21). Secondary structure prediction and helical wheel representation suggest that the region of TRIM14 from amino acids 29-46 may form such an amphipathic α-helix (Fig.…”

Section: Resultsmentioning

confidence: 99%

TRIM14 is a mitochondrial adaptor that facilitates retinoic acid-inducible gene-I–like receptor-mediated innate immune response

Zhou

Jia

Xue

et al. 2013

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

122

116

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Innate immunity provides the first line of host defense against invading microbial pathogens. This defense involves retinoic acidinducible gene-I-like receptors that detect viral RNA and activate the mitochondrial antiviral-signaling (MAVS) protein, an adaptor protein, leading to activation of the innate antiviral immune response. The mechanisms by which the MAVS signalosome assembles on mitochondria are only partially understood. Here, we identify tripartite motif 14 (TRIM14) as a mediator in the immune response against viral infection. TRIM14 localizes to the outer membrane of mitochondria and interacts with MAVS. Upon viral infection, TRIM14 undergoes Lys-63-linked polyubiquitination at Lys-365 and recruits NF-κB essential modulator to the MAVS signalosome, leading to the activation of both the IFN regulatory factor 3 and NF-κB pathways. Knockdown of TRIM14 disrupts the association between NF-κB essential modulator and MAVS and attenuates the antiviral response. Our results indicate that TRIM14 is a component of the mitochondrial antiviral immunity that facilitates the immune response mediated by retinoic acidinducible gene-I-like receptors.A ctivation of the innate immune response involves the detection of pathogen-associated molecular patterns (PAMPs), such as microbial nucleic acids, proteins, lipids, and carbohydrates. PAMPs are recognized by cellular pattern recognition receptors (PRRs), including Toll-like receptors, retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), NOD-like receptors, and C-type lectin receptors. Upon recognition, PRRs trigger a series of signaling events that lead to the induction of type I IFNs and proinflammatory cytokines (1).RLRs such as RIG-I and melanoma differentiation-associated antigen 5 (MDA5) recognize cytosolic viral RNA (2). Upon binding of RNA to the helicase domain, RIG-I or MDA5 undergoes a conformational change (3) and is recruited to the mitochondrial antiviral signaling (MAVS) adaptor. After binding of RIG-1 or MAD5, MAVS recruits various downstream molecules and further activates two kinase complexes: the noncanonical IκB kinases (IKKs) [TANK-binding kinase 1 (TBK1)/IKKi] and the canonical IKK complexes comprised of IKKα, IKK-β, and NF-κB essential modulator (NEMO) (4, 5). The TBK1/IKKi kinases phosphorylate IFN regulatory factor 3/7 (IRF3/7), which translocates to the nucleus and drives the transcription of IFNs (6). The canonical IKKs phosphorylate IκBα, resulting in the ubiquitination and proteasomal degradation of IκBα. NF-κB then is released to the nucleus and stimulates the expression of proinflammatory genes (7).MAVS-deficient mice show abolished virus-triggered induction of IFNs and increased susceptibility to viral infection (8), indicating that MAVS is essential for the innate immune response. MAVS consists of an N-terminal caspase activation and recruitment domain, a proline-rich domain, and a C-terminal transmembrane domain that targets it to the mitochondrial outer membrane (9). It has been suggested that the mitochondrial outer membrane pr...

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“…Hsp90 may facilitate translocation in addition to targeting (Young et al, 2003a;Fan et al, 2006). The Tom70 receptor recognizes preproteins with internal targeting sequences, including multiple targeting signals throughout a polypeptide sequence (Wiedemann et al, 2001;Neuport and Herrmann, 2007;Bolender et al, 2008).…”

Section: Mitochondrial Trafficking Of Erβmentioning

confidence: 99%

Estrogen actions on mitochondria—Physiological and pathological implications

Simpkins

Yang

Sarkar

et al. 2008

Molecular and Cellular Endocrinology

135

105

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Estrogens are potent neuroprotective hormones and mitochondria are the site of cellular life-death decisions. As such, it is not surprising that we and other have shown that estrogens have remarkable effects on mitochondrial function. Herein we provide evidence for a primary effect of estrogens on mitochondrial function, achieved in part by the import of estrogen receptor β (ERβ) into the mitochondria where it mediates a number of estrogen actions on this vital organelle. ERβ is imported into the mitochondria, through tethering to cytosolic chaperone protein and/or through direct interaction with mitochondrial import proteins. In the mitochondria, ERβ can affect transcription of critical mitochondrial genes through the interaction with estrogen response elements (ERE) or through protein-protein interactions with mitochondrially imported transcription factors. The potent effects of estrogens on mitochondrial function, particularly during mitochondrial stress, argues for a role of estrogens in the treatment of mitochondrial defects in chronic neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) and more acute conditions of mitochondrial compromise, like cerebral ischemia and traumatic brain injury.

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Multiple pathways for sorting mitochondrial precursor proteins

Cited by 289 publications

References 52 publications

Role of tyrosyl-DNA phosphodiesterase (TDP1) in mitochondria

Role of tyrosyl-DNA phosphodiesterase (TDP1) in mitochondria

TRIM14 is a mitochondrial adaptor that facilitates retinoic acid-inducible gene-I–like receptor-mediated innate immune response

Estrogen actions on mitochondria—Physiological and pathological implications

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