Translocase of inner mitochondrial membrane 44 alters the mitochondrial fusion and fission dynamics and protects from type 2 diabetes

Wang, Yu; Katayama, Akihiro; Terami, Takahiro; Han, Xiaoying; Nunoue, Tomokazu; Zhang, Dongxiao; Teshigawara, Sanae; Eguchi, Jun; Nakatsuka, Atsuko; Murakami, Kazutoshi; Ogawa, Daisuke; Furuta, Yasuhide; Makino, Hírofumi; Wada, Jun

doi:10.1016/j.metabol.2015.02.004

Cited by 20 publications

(24 citation statements)

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“…It has been demonstrated in the kidneys of streptozotocin-induced diabetic mice that there is an upregulation of translocase of inner mitochondrial membrane 44 (Timm44) [230]. Timm44 anchors mitochondrial heat-shock protein 70 to the translocase of inner mitochondrial membrane 23 complex and facilitates the import of mitochondria-targeted pre-proteins into the mitochondrial matrix.…”

Section: Mitochondrial Fusion and Fission Proteins In Cardiac Health mentioning

confidence: 99%

“…Over-expression of Timm44 in mice fed high-fat/high-sucrose chow protects from type 2 diabetes and obesity. Adipocyte size and pro-fission proteins were reduced while the pro-fusion proteins were induced when the mice were fed standard chow [230]. The discrepancy behind these varying levels of mitochondrial-shaping proteins in these mice when fed different diets remains unexplained although mitochondria ultimately became elongated.…”

Section: Mitochondrial Fusion and Fission Proteins In Cardiac Health mentioning

confidence: 99%

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Mitochondrial-Shaping Proteins in Cardiac Health and Disease – the Long and the Short of It!

Ong

Kalkhoran

Hernández‐Reséndiz

et al. 2017

Cardiovasc Drugs Ther

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Mitochondrial health is critically dependent on the ability of mitochondria to undergo changes in mitochondrial morphology, a process which is regulated by mitochondrial shaping proteins. Mitochondria undergo fission to generate fragmented discrete organelles, a process which is mediated by the mitochondrial fission proteins (Drp1, hFIS1, Mff and MiD49/51), and is required for cell division, and to remove damaged mitochondria by mitophagy. Mitochondria undergo fusion to form elongated interconnected networks, a process which is orchestrated by the mitochondrial fusion proteins (Mfn1, Mfn2 and OPA1), and which enables the replenishment of damaged mitochondrial DNA. In the adult heart, mitochondria are relatively static, are constrained in their movement, and are characteristically arranged into 3 distinct subpopulations based on their locality and function (subsarcolemmal, myofibrillar, and perinuclear). Although the mitochondria are arranged differently, emerging data supports a role for the mitochondrial shaping proteins in cardiac health and disease. Interestingly, in the adult heart, it appears that the pleiotropic effects of the mitochondrial fusion proteins, Mfn2 (endoplasmic reticulum-tethering, mitophagy) and OPA1 (cristae remodeling, regulation of apoptosis, and energy production) may play more important roles than their pro-fusion effects. In this review article, we provide an overview of the mitochondrial fusion and fission proteins in the adult heart, and highlight their roles as novel therapeutic targets for treating cardiac disease.

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Section: Mitochondrial Fusion and Fission Proteins In Cardiac Health mentioning

confidence: 99%

Section: Mitochondrial Fusion and Fission Proteins In Cardiac Health mentioning

confidence: 99%

Mitochondrial-Shaping Proteins in Cardiac Health and Disease – the Long and the Short of It!

Ong

Kalkhoran

Hernández‐Reséndiz

et al. 2017

Cardiovasc Drugs Ther

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“…Like other components of the TIM23 complex, Tim44 is a highly evolutionary conserved protein and is encoded by an essential gene. In mammals, Tim44 has been implicated in diabetes-associated metabolic and cellular abnormalities ( Wada and Kanwar, 1998 ; Wang et al, 2015 ). A novel therapeutic approach using gene delivery of Tim44 has recently shown promising results in mouse models of diabetic nephropathy ( Zhang et al, 2006 ).…”

Section: Introductionmentioning

confidence: 99%

Protein translocation channel of mitochondrial inner membrane and matrix-exposed import motor communicate via two-domain coupling protein

Banerjee

Gladkova

Mapa

et al. 2015

eLife

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The majority of mitochondrial proteins are targeted to mitochondria by N-terminal presequences and use the TIM23 complex for their translocation across the mitochondrial inner membrane. During import, translocation through the channel in the inner membrane is coupled to the ATP-dependent action of an Hsp70-based import motor at the matrix face. How these two processes are coordinated remained unclear. We show here that the two domain structure of Tim44 plays a central role in this process. The N-terminal domain of Tim44 interacts with the components of the import motor, whereas its C-terminal domain interacts with the translocation channel and is in contact with translocating proteins. Our data suggest that the translocation channel and the import motor of the TIM23 complex communicate through rearrangements of the two domains of Tim44 that are stimulated by translocating proteins.DOI: http://dx.doi.org/10.7554/eLife.11897.001

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“…The increase observed in the levels of proteins involved with mitochondrial network, namely Drp1 and MFN2, during 3T3-L1 differentiation provided a molecular support for the relevance of mitochondria dynamics in adipogenesis [82]. A recent study claims that mitochondria fusion is a good indication of energy expenditure augmentation and lower insulin resistance in adipocytes [119]. This was indicated by upregulation of Opa1, Mfn1 and Mfn2 genes [119].…”

mentioning

confidence: 84%

“…A recent study claims that mitochondria fusion is a good indication of energy expenditure augmentation and lower insulin resistance in adipocytes [119]. This was indicated by upregulation of Opa1, Mfn1 and Mfn2 genes [119]. Therefore, mitochondria remodeling during adipogenesis probably occurs to attend the energetic demand of lipid droplets formation.…”

mentioning

confidence: 99%

Mitochondrial Actions for Fat Browning and Energy Expenditure in White Adipose Tissue

Pbm¹,

Lopes²,

Alonso-Vale³

2016

Journal of Obesity and Overweight

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Obesity can be defined as the disruption in the balance between fuel intake and energy expenditure in favor of energy conservation. Together with type 2 diabetes (T2DM), these are the two of the most prevalent diseases affecting modern societies, arising mostly by changes in eating habits and a sedentary lifestyle associated with poorly known genetic determinants. Obesity predisposes to the so-called metabolic syndrome, which includes inflammation, hypertension, T2DM and cardiovascular diseases [1]. Obesity is imposing an increasingly heavy burden on the world's population in rich and poor nations alike, with almost 30 percent of people globally now either obese (BMI ≥ 30) or overweight (BMI ≥ 25) [2]. In fact, the number of overweight and obese people rose from 857 million in 1980 to 2.1 billion in 2013 [2]. Recently, obesity and metabolic syndrome were associated with mitochondrial dysfunction and deranged regulation of metabolic genes [3]. Interestingly, mitochondria of obese individuals seem to be different from those of lean individuals. Mitochondria from obese individuals display lower energy-generating capacity, less defined inner membranes and reduced fatty acid oxidation (FAO) [4]. AbstractWhite adipose tissue (WAT) is an endocrine organ with crucial role in the development of obesity and related diseases. White adipocytes have less mitochondria than brown adipocytes; nevertheless, there is an increasing body of evidence showing that mitochondrial parameters play a relevant role in WAT physiology, such as proliferation, differentiation and triacylglycerol storage levels. These parameters comprise mitochondria turnover, oxidative capacity, uncoupling, reactive oxygen species levels and oxygen consumption. In addition, the existence of beige (brown in white) adipose tissue and the transdifferatiation of WAT in brown adipose tissue are intrinsically related to mitochondria activity. Herein we highlight that the concerted action of stimulated lipolysis, mitochondrial oxidative metabolism and uncoupling (futile cycle) can enhance WAT energy expenditure. We consider WAT mitochondrial function a promising target for the development of therapies tackling lipotoxicity, obesity and related diseases. White adipose tissue (WAT) is the main tissue linked to obesity. WAT represents around 10% of total body weight in lean adults and more than 50% in obese individuals [5]. WAT is composed of mature adipocytes and the stromal-vascular fraction that contains preadipose cells (or adipoblasts), fibroblasts, immune cells, and blood vessel-associated cells [6]. A single and large lipid droplet occupies most of the white adipocyte volume and WAT copes with obesity either expanding (hypertrophy) or recruiting new cells (hyperplasia) [7]. WAT secretes an array of peptide hormones called adipokines (including leptin and adiponectin), which regulate neurological activities such as appetite and behavior, metabolic activities of peripheral tissues [8] and produce several pro-inflammatory cytokines, such as tumor necrosis factor alp...

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Translocase of inner mitochondrial membrane 44 alters the mitochondrial fusion and fission dynamics and protects from type 2 diabetes

Cited by 20 publications

References 38 publications

Mitochondrial-Shaping Proteins in Cardiac Health and Disease – the Long and the Short of It!

Mitochondrial-Shaping Proteins in Cardiac Health and Disease – the Long and the Short of It!

Protein translocation channel of mitochondrial inner membrane and matrix-exposed import motor communicate via two-domain coupling protein

Mitochondrial Actions for Fat Browning and Energy Expenditure in White Adipose Tissue

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