Dataset Information

3D reconstruction of murine mitochondria reveals changes in structure during aging linked to the MICOS complex.

ABSTRACT: During aging, muscle gradually undergoes sarcopenia, the loss of function associated with loss of mass, strength, endurance, and oxidative capacity. However, the 3D structural alterations of mitochondria associated with aging in skeletal muscle and cardiac tissues are not well described. Although mitochondrial aging is associated with decreased mitochondrial capacity, the genes responsible for the morphological changes in mitochondria during aging are poorly characterized. We measured changes in mitochondrial morphology in aged murine gastrocnemius, soleus, and cardiac tissues using serial block-face scanning electron microscopy and 3D reconstructions. We also used reverse transcriptase-quantitative PCR, transmission electron microscopy quantification, Seahorse analysis, and metabolomics and lipidomics to measure changes in mitochondrial morphology and function after loss of mitochondria contact site and cristae organizing system (MICOS) complex genes, Chchd3, Chchd6, and Mitofilin. We identified significant changes in mitochondrial size in aged murine gastrocnemius, soleus, and cardiac tissues. We found that both age-related loss of the MICOS complex and knockouts of MICOS genes in mice altered mitochondrial morphology. Given the critical role of mitochondria in maintaining cellular metabolism, we characterized the metabolomes and lipidomes of young and aged mouse tissues, which showed profound alterations consistent with changes in membrane integrity, supporting our observations of age-related changes in muscle tissues. We found a relationship between changes in the MICOS complex and aging. Thus, it is important to understand the mechanisms that underlie the tissue-dependent 3D mitochondrial phenotypic changes that occur in aging and the evolutionary conservation of these mechanisms between Drosophila and mammals.

SUBMITTER: Vue Z

PROVIDER: S-EPMC10726809 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

3D reconstruction of murine mitochondria reveals changes in structure during aging linked to the MICOS complex.

Vue Zer Z Garza-Lopez Edgar E Neikirk Kit K Katti Prasanna P Vang Larry L Beasley Heather H Shao Jianqiang J Marshall Andrea G AG Crabtree Amber A Murphy Alexandria C AC Jenkins Brenita C BC Prasad Praveena P Evans Chantell C Taylor Brittany B Mungai Margaret M Killion Mason M Stephens Dominique D Christensen Trace A TA Lam Jacob J Rodriguez Benjamin B Phillips Mark A MA Daneshgar Nastaran N Koh Ho-Jin HJ Koh Alice A Davis Jamaine J Devine Nina N Saleem Mohammad M Scudese Estevão E Arnold Kenneth Ryan KR Vanessa Chavarin Valeria V Daniel Robinson Ryan R Chakraborty Moumita M Gaddy Jennifer A JA Sweetwyne Mariya T MT Wilson Genesis G Zaganjor Elma E Kezos James J Dondi Cristiana C Reddy Anilkumar K AK Glancy Brian B Kirabo Annet A Quintana Anita M AM Dai Dao-Fu DF Ocorr Karen K Murray Sandra A SA Damo Steven M SM Exil Vernat V Riggs Blake B Mobley Bret C BC Gomez Jose A JA McReynolds Melanie R MR Hinton Antentor A

Aging cell 20231113 12

During aging, muscle gradually undergoes sarcopenia, the loss of function associated with loss of mass, strength, endurance, and oxidative capacity. However, the 3D structural alterations of mitochondria associated with aging in skeletal muscle and cardiac tissues are not well described. Although mitochondrial aging is associated with decreased mitochondrial capacity, the genes responsible for the morphological changes in mitochondria during aging are poorly characterized. We measured changes in ...[more]

PMID: 37960952

Similar Datasets

Project description:The liver, the largest internal organ and a metabolic hub, undergoes significant declines due to aging, affecting mitochondrial function and increasing the risk of systemic liver diseases. How the mitochondrial three-dimensional (3D) structure changes in the liver across aging, and the biological mechanisms regulating such changes confers remain unclear. In this study, we employed Serial Block Face-Scanning Electron Microscopy (SBF-SEM) to achieve high-resolution 3D reconstructions of murine liver mitochondria to observe diverse phenotypes and structural alterations that occur with age, marked by a reduction in size and complexity. We also show concomitant metabolomic and lipidomic changes in aged samples. Aged human samples reflected altered disease risk. To find potential regulators of this change, we examined the Mitochondrial Contact Site and Cristae Organizing System (MICOS) complex, which plays a crucial role in maintaining mitochondrial architecture. We observe that the MICOS complex is lost during aging, but not Sam50. Sam50 is a component of the sorting and assembly machinery (SAM) complex that acts in tandem with the MICOS complex to modulate cristae morphology. In murine models subjected to a high-fat diet, there is a marked depletion of the mitochondrial protein SAM50. This reduction in Sam50 expression may heighten the susceptibility to liver disease, as our human biobank studies corroborate that Sam50 plays a genetically regulated role in the predisposition to multiple liver diseases. We further show that changes in mitochondrial calcium dysregulation and oxidative stress accompany the disruption of the MICOS complex. Together, we establish that a decrease in mitochondrial complexity and dysregulated metabolism occur with murine liver aging. While these changes are partially be regulated by age-related loss of the MICOS complex, the confluence of a murine high-fat diet can also cause loss of Sam50, which contributes to liver diseases. In summary, our study reveals potential regulators that affect age-related changes in mitochondrial structure and metabolism, which can be targeted in future therapeutic techniques.

Project description:Impairments of mitochondrial functions are linked to human ageing and pathologies such as cancer, cardiomyopathy, neurodegeneration and diabetes. Specifically, aberrations in ultrastructure of mitochondrial inner membrane (IM) and factors regulating them are linked to diabetes. The development of diabetes is connected to the 'Mitochondrial Contact Site and Cristae Organising System' (MICOS) complex which is a large membrane protein complex defining the IM architecture. MIC26 and MIC27 are homologous apolipoproteins of the MICOS complex. MIC26 has been reported as a 22 kDa mitochondrial and a 55 kDa glycosylated and secreted protein. The molecular and functional relationship between these MIC26 isoforms has not been investigated. In order to understand their molecular roles, we depleted MIC26 using siRNA and further generated MIC26 and MIC27 knockouts (KOs) in four different human cell lines. In these KOs, we used four anti-MIC26 antibodies and consistently detected the loss of mitochondrial MIC26 (22 kDa) and MIC27 (30 kDa) but not the loss of intracellular or secreted 55 kDa protein. Thus, the protein assigned earlier as 55 kDa MIC26 is nonspecific. We further excluded the presence of a glycosylated, high-molecular weight MIC27 protein. Next, we probed GFP- and myc-tagged variants of MIC26 with antibodies against GFP and myc respectively. Again, only the mitochondrial versions of these tagged proteins were detected but not the corresponding high-molecular weight MIC26, suggesting that MIC26 is indeed not post-translationally modified. Mutagenesis of predicted glycosylation sites in MIC26 also did not affect the detection of the 55 kDa protein band. Mass spectrometry of a band excised from an SDS gel around 55 kDa could not confirm the presence of any peptides derived from MIC26. Taken together, we conclude that both MIC26 and MIC27 are exclusively localized in mitochondria and that the observed phenotypes reported previously are exclusively due to their mitochondrial function.

Project description:BackgroundPrognosis of stage IV colorectal cancer is related to control of liver metastasis. As of now, surgery provides survival advantage for patients affected by resectable colorectal liver metastases (CRLM), with parenchymal sparing strategies representing the most accepted strategy {[1]. In this setting, 3D reconstruction programs represent the newest available technological leap to improve anatomical accuracy [2]. Despite being quite expensive, 3D models have proved themselves as helpful adjunctive tools to enhance pre-operative strategy [3] in complex liver procedures, even in the eyes of expert hepatobiliary surgeons [4].MethodsWe present a video describing the practical use of a custom-made 3D model, acquired following specific quality criteria [2], for a case of bilateral CLRM after neoadjuvant chemotherapy.ResultsIn our reported case and as described in the video, pre-operative visualization of 3D reconstructions altered significantly the pre-operative surgical plan. First, following the principles of parenchymal sparing surgery, challenging atypical resections of metastatic lesions close to main vessels (right posterior branch of the portal vein, inferior vena cava) were preferred to anatomic resections/major hepatectomies, allowing the highest projected future liver remnant volume possible (up to 65%) amongst different available strategies. Secondly, the order of hepatic resections was planned to follow a decreasing degree of difficulty, in order minimize the effect of blood redistribution after previous resections during parenchymal dissection (thus starting from atypical resections close to main vessels, followed by anatomical resections and atypical resections of superficial resections). In addition, the availability of the 3D model in the operating room was crucial in the surgical field to guide safe surgical pathways, especially during atypical resections of lesions close to the main vessels: detection and navigation were further enhanced thanks to tools of augmented reality that allowed the surgeon to manipulate the 3D model through a touchless sensor in a dedicated screen in the operating room and to replicate a mirroring snapshot of the surgical field, without compromising sterility nor the surgical set-up. In the setting of these complex liver procedures, the application of 3D printed models has been described [4]; when available, 3D printed models, particularly useful in the pre-operative phase when explaining the procedure to patients and relatives, have been reported to have comparable significant impact, with feedback from expert hepatobiliary surgeons that is very similar to the one we are reporting in our experience [4].ConclusionRoutine use of 3D technology does not claim to revolutionize the world of traditional imaging but may be impactful in helping the surgeon visualize the anatomy of that specific individual in a dynamic and three-dimensional way that is similar to the surgical field, thus improving multidisciplinary preoperative planning and intraoperative navigation during complex liver surgery.

Dataset Information

3D reconstruction of murine mitochondria reveals changes in structure during aging linked to the MICOS complex.

Publications

3D reconstruction of murine mitochondria reveals changes in structure during aging linked to the MICOS complex.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets