Dataset Information

Synthetic Control of Mitochondrial Dynamics: Developing Three-Coordinate Au(I) Probes for Perturbation of Mitochondria Structure and Function.

ABSTRACT: Mitochondrial structure and organization is integral to maintaining mitochondrial homeostasis and an emerging biological target in aging, inflammation, neurodegeneration, and cancer. The study of mitochondrial structure and its functional implications remains challenging in part because of the lack of available tools for direct engagement, particularly in a disease setting. Here, we report a gold-based approach to perturb mitochondrial structure in cancer cells. Specifically, the design and synthesis of a series of tricoordinate Au(I) complexes with systematic modifications to group 15 nonmetallic ligands establish structure-activity relationships (SAR) to identify physiologically relevant tools for mitochondrial perturbation. The optimized compound, AuTri-9 selectively disrupts breast cancer mitochondrial structure rapidly as observed by transmission electron microscopy with attendant effects on fusion and fission proteins. This phenomenon triggers severe depolarization of the mitochondrial membrane in cancer cells. The high in vivo tolerability of AuTri-9 in mice demonstrates its preclinical utility. This work provides a basis for rational design of gold-based agents to control mitochondrial structure and dynamics.

SUBMITTER: Mertens RT

PROVIDER: S-EPMC8395693 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Synthetic Control of Mitochondrial Dynamics: Developing Three-Coordinate Au(I) Probes for Perturbation of Mitochondria Structure and Function.

Mertens R Tyler RT Jennings William C WC Ofori Samuel S Kim Jong Hyun JH Parkin Sean S Kwakye Gunnar F GF Awuah Samuel G SG

JACS Au 20210309 4

Mitochondrial structure and organization is integral to maintaining mitochondrial homeostasis and an emerging biological target in aging, inflammation, neurodegeneration, and cancer. The study of mitochondrial structure and its functional implications remains challenging in part because of the lack of available tools for direct engagement, particularly in a disease setting. Here, we report a gold-based approach to perturb mitochondrial structure in cancer cells. Specifically, the design and synt ...[more]

PMID: 34467306

Similar Datasets

Project description:Mitochondrial network is constantly in a dynamic and regulated balance of fusion and fission processes, which is known as mitochondrial dynamics. Mitochondria make physical contacts with almost every other membrane in the cell thus impacting cellular functions. Mutations in mitochondrial dynamics genes are known to cause neurogenetic diseases. To better understand the consequences on the cellular phenotype and pathophysiology of neurogenetic diseases associated with defective mitochondrial dynamics, we have compared the fibroblasts phenotypes of (i) patients carrying pathogenic variants in genes involved in mitochondrial dynamics such as DRP1 (also known as DNM1L), GDAP1, OPA1, and MFN2, and (ii) patients carrying mutated genes that their dysfunction affects mitochondria or induces a mitochondrial phenotype, but that are not directly involved in mitochondrial dynamic network, such as FXN (encoding frataxin, located in the mitochondrial matrix), MED13 (hyperfission phenotype), and CHKB (enlarged mitochondria phenotype). We identified mitochondrial network alterations in all patients' fibroblasts except for CHKB Q198*/Q198*. Functionally, all fibroblasts showed mitochondrial oxidative stress, without membrane potential abnormalities. The lysosomal area and distribution were abnormal in GDAP1 W67L/W67L, DRP1 K75E/+, OPA1 F570L/+, and FXN R165C/GAA fibroblasts. These lysosomal alterations correlated with mitochondria-lysosome membrane contact sites (MCSs) defects in GDAP1 W67L/W67L exclusively. The study of mitochondrial contacts in all samples further revealed a significant decrease in MFN2 R104W/+ fibroblasts. GDAP1 and MFN2 are outer mitochondrial membrane (OMM) proteins and both are related to Charcot-Marie Tooth neuropathy. Here we identified their constitutive interaction as well as MFN2 interaction with LAMP-1. Therefore MFN2 is a new mitochondria-lysosome MCSs protein. Interestingly, GDAP1 W67L/W67L and MFN2 R104W/+ fibroblasts carry pathogenic changes that occur in their catalytic domains thus suggesting a functional role of GDAP1 and MFN2 in mitochondria-lysosome MCSs. Finally, we observed starvation-induced autophagy alterations in DRP1 K75E/+, GDAP1 W67L/W67L, OPA1 F570L/+, MFN2 R104W/+, and CHKB Q198*/Q198* fibroblasts. These genes are related to mitochondrial membrane structure or lipid composition, which would associate the OMM with starvation-induced autophagy. In conclusion, the study of mitochondrial dynamics and mitochondria-lysosome axis in a group of patients with different neurogenetic diseases has deciphered common and unique cellular phenotypes of degrading and non-degrading pathways that shed light on pathophysiological events, new biomarkers and pharmacological targets for these disorders.

Dataset Information

Synthetic Control of Mitochondrial Dynamics: Developing Three-Coordinate Au(I) Probes for Perturbation of Mitochondria Structure and Function.

Publications

Synthetic Control of Mitochondrial Dynamics: Developing Three-Coordinate Au(I) Probes for Perturbation of Mitochondria Structure and Function.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets