Thomas MacVicar

Bio: Thomas MacVicar is an academic researcher from Max Planck Society. The author has contributed to research in topics: Mitochondrion & Mitochondrial DNA. The author has an hindex of 10, co-authored 16 publications receiving 600 citations. Previous affiliations of Thomas MacVicar include University of Cologne.

OPA1 processing in cell death and disease – the long and short of it

Abstract: The regulation of mitochondrial dynamics by the GTPase OPA1, which is located at the inner mitochondrial membrane, is crucial for adapting mitochondrial function and preserving cellular health. OPA1 governs the delicate balance between fusion and fission in the dynamic mitochondrial network. A disturbance of this balance, often observed under stress and pathologic conditions, causes mitochondrial fragmentation and can ultimately result in cell death. As discussed in this Commentary, these morphological changes are regulated by proteolytic processing of OPA1 by the inner-membrane peptidases YME1L (also known as YME1L1) and OMA1. Long, membrane-bound forms of OPA1 are required for mitochondrial fusion, but their processing to short, soluble forms limits fusion and can facilitate mitochondrial fission. Excessive OPA1 processing by the stress-activated protease OMA1 promotes mitochondrial fragmentation and, if persistent, triggers cell death and tissue degeneration in vivo The prevention of OMA1-mediated OPA1 processing and mitochondrial fragmentation might thus offer exciting therapeutic potential for human diseases associated with mitochondrial dysfunction.

Instant Clue: A Software Suite for Interactive Data Visualization and Analysis.

Abstract: The development of modern high-throughput instrumentation and improved core facility infrastructures leads to an accumulation of large amounts of scientific data. However, for a majority of scientists the comprehensive analysis and visualization of their data goes beyond their expertise. To reduce this hurdle, we developed a software suite called Instant Clue that helps scientists to visually analyze data and to gain insights into biological processes from their high-dimensional dataset. Instant Clue combines the power of visual and statistical analytics using a straight forward drag & drop approach making the software highly intuitive. Additionally, it offers a comprehensive portfolio of statistical tools for systematic analysis such as dimensional reduction, (un)-supervised learning, clustering, multi-block (omics) integration and curve fitting. Charts can be combined with high flexibility into a main figure template for direct usage in scientific publications. Even though Instant Clue was developed with the omics-sciences in mind, users can analyze any kind of data from low to high dimensional data sets. The open-source software is available for Windows and Mac OS ( http://www.instantclue.uni-koeln.de ) and is accompanied by a detailed video tutorial series.

Lipid signalling drives proteolytic rewiring of mitochondria by YME1L.

Abstract: Reprogramming of mitochondria provides cells with the metabolic flexibility required to adapt to various developmental transitions such as stem cell activation or immune cell reprogramming, and to respond to environmental challenges such as those encountered under hypoxic conditions or during tumorigenesis1-3. Here we show that the i-AAA protease YME1L rewires the proteome of pre-existing mitochondria in response to hypoxia or nutrient starvation. Inhibition of mTORC1 induces a lipid signalling cascade via the phosphatidic acid phosphatase LIPIN1, which decreases phosphatidylethanolamine levels in mitochondrial membranes and promotes proteolysis. YME1L degrades mitochondrial protein translocases, lipid transfer proteins and metabolic enzymes to acutely limit mitochondrial biogenesis and support cell growth. YME1L-mediated mitochondrial reshaping supports the growth of pancreatic ductal adenocarcinoma (PDAC) cells as spheroids or xenografts. Similar changes to the mitochondrial proteome occur in the tumour tissues of patients with PDAC, suggesting that YME1L is relevant to the pathophysiology of these tumours. Our results identify the mTORC1-LIPIN1-YME1L axis as a post-translational regulator of mitochondrial proteostasis at the interface between metabolism and mitochondrial dynamics.

Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation

Abstract: Mitochondriopathies often present clinically as multisystemic disorders of primarily high-energy consuming organs. Assembly, turnover, and surveillance of mitochondrial proteins are essential for mitochondrial function and a key task of AAA family members of metalloproteases. We identified a homozygous mutation in the nuclear encoded mitochondrial escape 1-like 1 gene YME1L1, member of the AAA protease family, as a cause of a novel mitochondriopathy in a consanguineous pedigree of Saudi Arabian descent. The homozygous missense mutation, located in a highly conserved region in the mitochondrial pre-sequence, inhibits cleavage of YME1L1 by the mitochondrial processing peptidase, which culminates in the rapid degradation of YME1L1 precursor protein. Impaired YME1L1 function causes a proliferation defect and mitochondrial network fragmentation due to abnormal processing of OPA1. Our results identify mutations in YME1L1 as a cause of a mitochondriopathy with optic nerve atrophy highlighting the importance of YME1L1 for mitochondrial functionality in humans.

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

Abstract: Metabolism rewiring is an important hallmark of cancers. Being one of the most abundant free amino acids in the human blood, glutamine supports bioenergetics and biosynthesis, tumor growth, and the production of antioxidants through glutaminolysis in cancers. In glutamine dependent cancer cells, more than half of the tricarboxylic/critic acid (TCA) metabolites are derived from glutamine. Glutaminolysis controls the process of converting glutamine into TCA cycle metabolites through the regulation of multiple enzymes, among which the glutaminase shows the importance as the very first step in this process. Targeting glutaminolysis via glutaminase inhibition emerges as a promising strategy to disrupt cancer metabolism and tumor progression. Here, we review the regulation of glutaminase and the role of glutaminase in cancer metabolism and metastasis. Furthermore, we highlight the glutaminase inhibitor based metabolic therapy strategy and their potential applications in clinical scenarios.

mTOR Signaling in Growth, Metabolism, and Disease

Abstract: The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

Mitochondrial dynamics: overview of molecular mechanisms

Abstract: Mitochondria are highly dynamic organelles undergoing coordinated cycles of fission and fusion, referred as ‘mitochondrial dynamics’, in order to maintain their shape, distribution and size Their transient and rapid morphological adaptations are crucial for many cellular processes such as cell cycle, immunity, apoptosis and mitochondrial quality control Mutations in the core machinery components and defects in mitochondrial dynamics have been associated with numerous human diseases These dynamic transitions are mainly ensured by large GTPases belonging to the Dynamin family Mitochondrial fission is a multi-step process allowing the division of one mitochondrion in two daughter mitochondria It is regulated by the recruitment of the GTPase Dynamin-related protein 1 (Drp1) by adaptors at actin- and endoplasmic reticulum-mediated mitochondrial constriction sites Drp1 oligomerization followed by mitochondrial constriction leads to the recruitment of Dynamin 2 to terminate membrane scission Inner mitochondrial membrane constriction has been proposed to be an independent process regulated by calcium influx Mitochondrial fusion is driven by a two-step process with the outer mitochondrial membrane fusion mediated by mitofusins 1 and 2 followed by inner membrane fusion, mediated by optic atrophy 1 In addition to the role of membrane lipid composition, several members of the machinery can undergo post-translational modifications modulating these processes Understanding the molecular mechanisms controlling mitochondrial dynamics is crucial to decipher how mitochondrial shape meets the function and to increase the knowledge on the molecular basis of diseases associated with morphology defects This article will describe an overview of the molecular mechanisms that govern mitochondrial fission and fusion in mammals

Multi-omics Data Integration, Interpretation, and Its Application.

Abstract: To study complex biological processes holistically, it is imperative to take an integrative approach that combines multi-omics data to highlight the interrelationships of the involved biomolecules and their functions. With the advent of high-throughput techniques and availability of multi-omics data generated from a large set of samples, several promising tools and methods have been developed for data integration and interpretation. In this review, we collected the tools and methods that adopt integrative approach to analyze multiple omics data and summarized their ability to address applications such as disease subtyping, biomarker prediction, and deriving insights into the data. We provide the methodology, use-cases, and limitations of these tools; brief account of multi-omics data repositories and visualization portals; and challenges associated with multi-omics data integration.