Mutations of the mitochondrial carrier translocase channel subunit TIM22 cause early-onset mitochondrial myopathy

Pacheu-Grau, David; Callegari, Sylvie; Emperador, Sonia; Thompson, Kyle; Aich, Abhishek; Topol, Sarah E.; Spencer, Emily; McFarland, Robert; Ruiz‐Pesini, Eduardo; Torkamani, Ali; Taylor, Robert W.; Montoya, Julio; Rehling, Peter

doi:10.1093/hmg/ddy305

Cited by 28 publications

(37 citation statements)

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“…Mutations in the TIMM8A gene (also known as DDP1 encoding a small chaperone homologue TIM8A) cause deafness dystonia syndrome 49,50 . Recently, mutations in the TIM22 gene have been identified to cause early-onset mitochondrial myopathy 51 .…”

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confidence: 99%

Cryo-EM Structure of the Human Mitochondrial Translocase TIM22 Complex

Wang

Guan

et al. 2019

Preprint

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21Mitochondria play vital functions in cellular metabolism, homeostasis, and apoptosis 1-3 . 22 Most of the mitochondrial proteins are synthesized as precursors in the cytosol and 23 imported into mitochondria for folding or maturation 4,5 . The translocase TIM22 24 complex is responsible for the import of multiple hydrophobic carrier proteins that are 25 then folded in the inner membrane of mitochondria 6-8 . In mammalian cells, the TIM22 26 complex consists of at least six components, Tim22, Tim29, AGK, and three Tim 27 chaperones (Tim9, Tim10a and Tim10b) 9-14 . Here, we report the cryo-EM structure of 28 the human translocase TIM22 complex at an overall resolution of 3.7 angstrom. The 29 core subunit, Tim22, contains four transmembrane helices, forming a partial pore that is 30 open to the lipid bilayer. Tim29 is a single transmembrane protein that provides an 31 N-terminal helix to stabilize Tim22 and a C-terminal intermembrane space (IMS) 32 domain to connect AGK and two TIM chaperone hexamers to maintain complex 33 integrity. One TIM hexamer comprises Tim9 and Tim10a in a 3:3 molar ratio, and the 34 other consists of two Tim9 units, three Tim10a units, and one Tim10b unit. The latter 35 hexamer faces the intramembrane region of Tim22, likely providing the dock to load the 36 precursors to the partial pore of Tim22. Our structure serves as a molecular basis for 37 the mechanistic understanding of TIM22 complex function. 38 39 40 3Mitochondria are essential eukaryotic cellular organelles with multiple vital functions, 41 such as energetics, metabolism, and cellular signaling 1,2 . These functions are performed by 42 more than 1,000 proteins 3,5 . However, only a small set of these proteins are synthesized in the 43 mitochondria; most of the mitochondria functioning proteins (~99%) are encoded by nuclear 44 genes, and imported into the correct mitochondrial compartment by specific preprotein 45 translocase complexes 3,5,15,16 . These complexes include the translocase of outer membrane 46 (the TOM complex) 17-20 , the carrier translocase of inner membrane complex (the TIM22 47 7 toward the intermembrane space and interact with the Tim9/10a/10b hexamer. Helix 1 and 129 loop 1, similar to a hook, sinuously wind around the groove between the inner helices and the 130 outer helices of Tim9 and Tim10a. Helix 1 was nestled in a greasy pocket formed by Tim9 131 and Tim10a (Fig. 2b), and likely functioned as a plug to obstruct the hydrophobic carrier 132 precursor from wedging within the hexamer chaperone from this side (Extended Data Fig. 6a). 133The recently identified disease-related mutation (Val33Leu) of Tim22 was located in the helix 134 1 51 . 135 136 Specific interactions comprise van der Waals contacts and one hydrogen bond. 137

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confidence: 99%

Cryo-EM Structure of the Human Mitochondrial Translocase TIM22 Complex

Wang

Guan

et al. 2019

Preprint

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“…Protein import is an elaborate process (67). Protein import efficiency is expected to be directly or indirectly affected in many human diseases (68)(69)(70)(71)(72). More broadly, aging is also associated with reduced protein import (73).…”

Section: Discussionmentioning

confidence: 99%

Cytosolic Adaptation to Mitochondrial Precursor Overaccumulation Stress Induces Progressive Muscle Wasting

Chen

Wang

Middleton

et al. 2019

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Mitochondrial dysfunction causes muscle wasting (or atrophy) in many diseases and probably also during aging. The underlying mechanism is unclear. Accumulating evidence suggests that substantial levels of bioenergetic deficiency and oxidative stress are insufficient by themselves to intrinsically cause muscle wasting, raising the possibility that non-bioenergetic factors may contribute to mitochondria-induced muscle wasting. In this report, we show that chronic adaptation to mitochondria-induced proteostatic stress in the cytosol induces muscle wasting. We generated transgenic mice with unbalanced mitochondrial protein loading and import, by a two-fold increase in the expression of the nuclear-encoded mitochondrial carrier protein, Ant1. We found that the ANT1-transgenic mice progressively lose muscle mass. Skeletal muscle is severely atrophic in older mice without affecting the overall lifespan. Mechanistically, Ant1 overloading induces aggresome-like structures and the expression of small heat shock proteins in the cytosol. The data support mitochondrial Precursor Overaccumulation Stress (mPOS), a recently discovered cellular stress mechanism caused by the toxic accumulation of unimported mitochondrial precursors/preproteins. Importantly, the ANT1-transgenic muscles have a drastically remodeled transcriptome that appears to be trying to counteract mPOS, by repressing protein synthesis, and by stimulating proteasomal function, autophagy and lysosomal amplification. These anti-mPOS responses collectively reduce protein content, which is known to decrease myofiber size and muscle mass. Our work therefore revealed that a subtle imbalance between mitochondrial protein load and import is sufficient to induce mPOS in vivo, and that anti-mPOS adaptation is a robust mechanism of muscle wasting. This finding may help improve the understanding of how mitochondria contribute to muscle wasting. It could have direct implications for several human diseases associated with ANT1 overexpression, including Facioscapulohumeral Dystrophy (FSHD).

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“…HEK293T Flp-In™ T-REX™ were purchased from Invitrogen. WT fibroblasts, COA6 KO HEK293T, WT and Rho0-143B cell lines were previously reported (Pacheu-Grau et al, 2018; 2020; Gómez-Durán et al, 2010; King and Attardi, 1989). The G6930A 143B cell line was a gift from G. Manfredi and J. Montoya (Bruno et al, 1999; Richter-Dennerlein et al, 2016).…”

Section: Methodsmentioning

confidence: 99%

Local translation in synaptic mitochondria influences synaptic transmission

Yousefi

Fornasiero

Cyganek

et al. 2020

Preprint

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Mitochondria possess a small genome that codes for core subunits of the oxidative phosphorylation system, and whose expression is essential for energy production. Information on the regulation and spatial organization of mitochondrial gene expression in the cellular context has been difficult to obtain. Here we addressed this by devising an imaging approach to analyze mitochondrial translation, by following the incorporation of clickable non-canonical amino acids. We applied this method to multiple cell types, including hippocampal neurons, where we found ample evidence for mitochondrial translation in both dendrites and axons. Translation levels were surprisingly heterogeneous, were typically stronger in axons, and were independent of their distance from the cell soma, where mitochondria presumably descent from. Presynaptic mitochondrial translation correlated with local synaptic activity, and blocking mitochondria translation reduced synaptic function. Overall, these findings demonstrate that mitochondrial gene expression in neurons is intimately linked to neuronal function.

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Mutations of the mitochondrial carrier translocase channel subunit TIM22 cause early-onset mitochondrial myopathy

Cited by 28 publications

References 48 publications

Cryo-EM Structure of the Human Mitochondrial Translocase TIM22 Complex

Cryo-EM Structure of the Human Mitochondrial Translocase TIM22 Complex

Cytosolic Adaptation to Mitochondrial Precursor Overaccumulation Stress Induces Progressive Muscle Wasting

Local translation in synaptic mitochondria influences synaptic transmission

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