scispace - formally typeset
Search or ask a question
Author

Ming Chen

Bio: Ming Chen is an academic researcher from University of Tennessee. The author has contributed to research in topics: Mitochondrial fission & Mitochondrion. The author has an hindex of 14, co-authored 26 publications receiving 1856 citations. Previous affiliations of Ming Chen include Baylor University & Chinese Academy of Sciences.

Papers
More filters
Journal ArticleDOI
TL;DR: It is reported that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy, and its findings offer insights into mitochondrial quality control in mammalian cells.
Abstract: Accumulating evidence has shown that dysfunctional mitochondria can be selectively removed by mitophagy. Dysregulation of mitophagy is implicated in the development of neurodegenerative disease and metabolic disorders. How individual mitochondria are recognized for removal and how this process is regulated remain poorly understood. Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. FUNDC1 interacted with LC3 through its typical LC3-binding motif Y(18)xxL(21), and mutation of the LC3-interaction region impaired its interaction with LC3 and the subsequent induction of mitophagy. Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. Mechanistic studies further revealed that hypoxia induced dephosphorylation of FUNDC1 and enhanced its interaction with LC3 for selective mitophagy. Our findings thus offer insights into mitochondrial quality control in mammalian cells.

1,142 citations

Journal ArticleDOI
TL;DR: The data suggest that FUNDC1 regulates both mitochondrial fission or fusion and mitophagy and mediates the “coupling” across the double membrane for mitochondrial dynamics and quality control.
Abstract: Mitochondrial fragmentation due to imbalanced fission and fusion of mitochondria is a prerequisite for mitophagy, however, the exact “coupling” of mitochondrial dynamics and mitophagy remains unclear. We have previously identified that FUNDC1 recruits MAP1LC3B/LC3B (LC3) through its LC3-interacting region (LIR) motif to initiate mitophagy in mammalian cells. Here, we show that FUNDC1 interacts with both DNM1L/DRP1 and OPA1 to coordinate mitochondrial fission or fusion and mitophagy. OPA1 interacted with FUNDC1 via its Lys70 (K70) residue, and mutation of K70 to Ala (A), but not to Arg (R), abolished the interaction and promoted mitochondrial fission and mitophagy. Mitochondrial stress such as selenite or FCCP treatment caused the disassembly of the FUNDC1-OPA1 complex while enhancing DNM1L recruitment to the mitochondria. Furthermore, we observed that dephosphorylation of FUNDC1 under stress conditions promotes the dissociation of FUNDC1 from OPA1 and association with DNM1L. Our data suggest that ...

288 citations

Journal ArticleDOI
TL;DR: This study proposed similar nature of drug combinations: principal drugs which obtain synergistic effect with similar adjuvant drugs are often similar and vice versa and developed a novel algorithm termed Network-based Laplacian regularized Least Square Synergistic drug combination prediction (NLLSS) to predict potential synergistic drug combinations by integrating different kinds of information.
Abstract: Fungal infection has become one of the leading causes of hospital-acquired infections with high mortality rates. Furthermore, drug resistance is common for fungus-causing diseases. Synergistic drug combinations could provide an effective strategy to overcome drug resistance. Meanwhile, synergistic drug combinations can increase treatment efficacy and decrease drug dosage to avoid toxicity. Therefore, computational prediction of synergistic drug combinations for fungus-causing diseases becomes attractive. In this study, we proposed similar nature of drug combinations: principal drugs which obtain synergistic effect with similar adjuvant drugs are often similar and vice versa. Furthermore, we developed a novel algorithm termed Network-based Laplacian regularized Least Square Synergistic drug combination prediction (NLLSS) to predict potential synergistic drug combinations by integrating different kinds of information such as known synergistic drug combinations, drug-target interactions, and drug chemical structures. We applied NLLSS to predict antifungal synergistic drug combinations and showed that it achieved excellent performance both in terms of cross validation and independent prediction. Finally, we performed biological experiments for fungal pathogen Candida albicans to confirm 7 out of 13 predicted antifungal synergistic drug combinations. NLLSS provides an efficient strategy to identify potential synergistic antifungal combinations.

213 citations

Journal ArticleDOI
TL;DR: Resistance to all the tested antimicrobials, except carbapenems and amikacin, was observed in a proportion of hvKP strains, 17% (5/29) of which expressed extended-spectrum β-lactamase, indicating an increasing propensity for the acquisition of antimicrobial resistance.
Abstract: BACKGROUND: New hypervirulent variants of Klebsiella pneumoniae (hvKP) are emerging globally, most of which exhibit antimicrobial susceptibility. METHODS: A retrospective study was conducted in 88 patients with cultures positive for K. pneumoniae hospitalized in the Beijing You'an Hospital from April 2010 to June 2012. The clinical and molecular data of the hvKP isolates (defined as string test positive) were compared with those of the classic K. pneumoniae (cKP) isolates. RESULTS: Overall, 33.0% (29/88) of K. pneumoniae isolates were hvKP. Univariate analysis revealed the following risk factors for hvKP: virulence gene rmpA (odds ratio [OR], 16.92 [95% confidence interval {CI}, 4.842-59.145]), capsule antigens K1 (OR, 3.355 [95% CI, 1.153-9.768]) and K2 (OR, 9.280 [95% CI, 0.987-87.250]), alcoholic hepatitis (OR, 7.435 [95% CI, 1.397-39.572]), liver abscess (OR, 9.068 [95% CI, 1.747-47.061]), metastatic infection (OR, 2.752 [95% CI, 1.100-6.886]), community-acquired infection (OR, 10.432 [95% CI, 3.623-30.033]), sputum isolation (OR, 0.312 [95% CI, .095-1.021]), and HIV infection (<0.001 [not applicable]). Multivariate analysis implicated rmpA (OR, 17.398 [95% CI, 4.224-71.668]) and community-acquired infection (OR, 6.844 [95% CI, 1.905-24.585]) as independent risk factors. The proportion of hvKP isolates increased from April to December 2010, January to September 2011, and October 2011 to June 2012 (to 25.5%, 26.7%, and 54.5%, respectively). Resistance to 14 of 19 tested antimicrobials was found to be significantly greater in cKP compared to hvKP. Importantly, resistance to all the tested antimicrobials, except carbapenems and amikacin, was observed in a proportion of hvKP strains, 17% (5/29) of which expressed extended-spectrum β-lactamase. Furthermore, antimicrobial resistance in hvKP strains increased over time. CONCLUSIONS: HvKP strains are being isolated from patients in China with increasing frequency and constitute an increasing proportion of K. pneumoniae strains, indicating an increasing propensity for the acquisition of antimicrobial resistance.

211 citations

Journal ArticleDOI
TL;DR: A diterpenoid derivative 15-oxospiramilactone (S3) is identified that potently induced mitochondrial fusion to restore the mitochondrial network and oxidative respiration in cells that are deficient in either Mfn1 or Mfn2.
Abstract: Mitochondrial fusion is a highly coordinated process that mixes and unifies the mitochondrial compartment for normal mitochondrial functions and mitochondrial DNA inheritance. Dysregulated mitochondrial fusion causes mitochondrial fragmentation, abnormal mitochondrial physiology and inheritance, and has been causally linked with a number of neuronal diseases. Here, we identified a diterpenoid derivative 15-oxospiramilactone (S3) that potently induced mitochondrial fusion to restore the mitochondrial network and oxidative respiration in cells that are deficient in either Mfn1 or Mfn2. A mitochondria-localized deubiquitinase USP30 is a target of S3. The inhibition of USP30 by S3 leads to an increase of non-degradative ubiquitination of Mfn1/2, which enhances Mfn1 and Mfn2 activity and promotes mitochondrial fusion. Thus, through the use of an inhibitor of USP30, our study uncovers an unconventional function of non-degradative ubiquitination of Mfns in promoting mitochondrial fusion.

154 citations


Cited by
More filters
Journal Article
Fumio Tajima1
30 Oct 1989-Genomics
TL;DR: It is suggested that the natural selection against large insertion/deletion is so weak that a large amount of variation is maintained in a population.

11,521 citations

Journal Article
TL;DR: For the next few weeks the course is going to be exploring a field that’s actually older than classical population genetics, although the approach it’ll be taking to it involves the use of population genetic machinery.
Abstract: So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

9,847 citations

Journal ArticleDOI
Daniel J. Klionsky1, Kotb Abdelmohsen2, Akihisa Abe3, Joynal Abedin4  +2519 moreInstitutions (695)
TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

5,187 citations

Journal ArticleDOI
TL;DR: The relevance of these pathways in neurons where defects in mitophagy have been implicated in neurodegeneration are discussed, in addition to the importance of identifying specific regulators ofMitophagy that ensure selective sequestration of mitochondria as cargo.
Abstract: Selective autophagy of mitochondria, known as mitophagy, is an important mitochondrial quality control mechanism that eliminates damaged mitochondria. Mitophagy also mediates removal of mitochondria from developing erythrocytes, and contributes to maternal inheritance of mitochondrial DNA through the elimination of sperm-derived mitochondria. Recent studies have identified specific regulators of mitophagy that ensure selective sequestration of mitochondria as cargo. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the autophagic machinery to mitochondria, while mammalian Nix is required for degradation of erythrocyte mitochondria. The elimination of damaged mitochondria in mammals is mediated by a pathway comprised of PTEN-induced putative protein kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. PINK1 and Parkin accumulate on damaged mitochondria, promote their segregation from the mitochondrial network, and target these organelles for autophagic degradation in a process that requires Parkin-dependent ubiquitination of mitochondrial proteins. Here we will review recent advances in our understanding of the different pathways of mitophagy. In addition, we will discuss the relevance of these pathways in neurons where defects in mitophagy have been implicated in neurodegeneration.

1,178 citations