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Abeliovich, H. New gadget in the membrane trafficking toolbox: A novel inhibitor of SNARE priming. Journal of Biological Chemistry 2019, 294, 17186-17187. Publisher's VersionAbstract
NSF (N-ethylmaleimide sensitive factor) and its yeast counterpart Sec18 are highly conserved homohexameric proteins that play vital roles in eukaryotic membrane trafficking. Sec18 functions by disrupting SNARE complexes formed in cis, on the same membrane. However, the molecular mechanisms of this process are poorly understood, in large part due to the lack of selective, reversible inhibitors. A new study by Sparks et al. now reports a small molecule that appears to selectively inhibit Sec18 action in an in vitro assay. Their finding now paves the way to elucidate further details of Sec18-mediated SNARE priming. © 2019 Abeliovich.
Kolitsida, P. ; Zhou, J. ; Rackiewicz, M. ; Nolic, V. ; Dengjel, J. ; Abeliovich, H. Phosphorylation of mitochondrial matrix proteins regulates their selective mitophagic degradation. Proceedings of the National Academy of Sciences 2019. Publisher's VersionAbstract
Mitochondrial dysfunction underlies many age-related human pathologies. In normal cells, defective mitochondria are often degraded by mitophagy, a process in which these mitochondria are engulfed in autophagosomes and sent for degradation in the lysosome/vacuole. Surprisingly, studies on mitophagy in diverse eukaryotic organisms reveal an unexpected dimension of protein-level selectivity, wherein individual protein species exhibit divergent rates of mitophagic degradation. In this report, we show that this surprising intramitochondrial selectivity can be generated by differential phosphorylation of individual mitochondrial protein species, and we identify mitochondrial phosphatases and kinases that contribute to this regulation. By identifying a mechanism that regulates the intramitochondrial selectivity of mitophagic degradation, our findings open the door to potential manipulation of the quality-control process in the future.Mitophagy is an important quality-control mechanism in eukaryotic cells, and defects in mitophagy correlate with aging phenomena and neurodegenerative disorders. It is known that different mitochondrial matrix proteins undergo mitophagy with very different rates but, to date, the mechanism underlying this selectivity at the individual protein level has remained obscure. We now present evidence indicating that protein phosphorylation within the mitochondrial matrix plays a mechanistic role in regulating selective mitophagic degradation in yeast via involvement of the Aup1 mitochondrial protein phosphatase, as well as 2 known matrix-localized protein kinases, Pkp1 and Pkp2. By focusing on a specific matrix phosphoprotein reporter, we also demonstrate that phospho-mimetic and nonphosphorylatable point mutations at known phosphosites in the reporter increased or decreased its tendency to undergo mitophagy. Finally, we show that phosphorylation of the reporter protein is dynamically regulated during mitophagy in an Aup1-dependent manner. Our results indicate that structural determinants on a mitochondrial matrix protein can govern its mitophagic fate, and that protein phosphorylation regulates these determinants.
Kolitsida, P. ; Abeliovich, H. Methods for Studying Mitophagy in Yeast. In Autophagy: Methods and Protocols; Ktistakis, N. ; Florey, O., Ed. Autophagy: Methods and Protocols; Springer New York: New York, NY, 2019; pp. 669 - 678. Publisher's VersionAbstract
Under some experimental conditions, eukaryotic cells, from yeast to man, will digest a portion of their mitochondrial cohort through an autophagic process termed mitophagy. In humans, defects in mitophagy have been proposed to play a causative role in a number of late-onset degenerative diseases such as Parkinson’s disease and type II diabetes. As a consequence the study of mitophagy, as a quality control process in eukaryotic cells, has become an increasingly important focus in contemporary cell biology. When faced with the task of assaying mitophagy in yeast, the experimentalist has at his or her disposal a variety of induction conditions and assay systems to choose from. Here, we survey several well-established protocols for inducing and monitoring mitophagy in the yeast Saccharomyces cerevisiae and discuss their relative merits, limitations, and potential pitfalls.
Dengjel, J. ; Abeliovich, H. Roles of mitophagy in cellular physiology and development. 2017, 367, 95 - 109. Publisher's VersionAbstract
The autophagic degradation of mitochondria, or mitophagy, has been shown to occur in eukaryotic cells under various physiological conditions. Broadly, these fall into two categories: quality-control related mitophagy and developmentally induced mitophagy. Quality-control related mitophagy, which is the lysosomal/vacuolar degradation of malfunctioning or superfluous mitochondria, is an important housekeeping function in respiring eukaryotic cells. It plays an essential role in physiological homeostasis and its deregulation has been linked to the progression of late-onset diseases. On the other hand, developmental processes such as reticulocyte maturation have also been shown to involve mitophagy. Importantly, there are clear differences between these processes. Unlike our knowledge of the more general degradation of soluble cytosolic content during starvation-induced macroautophagy, the mechanisms involved in the selective autophagic degradation of mitochondria have only recently begun to receive significant attention. Here, we review the current literature on these topics and proceed to provide specific examples from yeast and mammalian systems. Finally, we cover experimental approaches, with a focus on proteomic methods dedicated to the study of mitophagy in different systems.
Kolitsida, P. ; Abeliovich, H. Selective emodin toxicity in cancer cells. Oncotarget 2017, 8 36932-36933.
Shen, Z. ; Li, Y. ; Gasparski, A. N. ; Abeliovich, H. ; Greenberg, M. L. Cardiolipin Regulates Mitophagy through the Protein Kinase C Pathway. Journal of Biological Chemistry 2017, 292, 2916-2923. Publisher's VersionAbstract
Cardiolipin (CL), the signature phospholipid of mitochondrial membranes, is important for cardiovascular health, and perturbation of CL metabolism is implicated in cardiovascular disease. Although the role of CL in mitochondrial function, biogenesis, and genome stability has been studied, recent findings indicate that it is essential for functions apart from mitochondrial bioenergetics. In this study, we report that mitophagy is perturbed in CL-deficient yeast cells. Mutants of autophagy/mitophagy genes ATG8, ATG18, and ATG32 synthetically interact with CL synthase mutant crd1Δ. CL-deficient cells exhibited decreased GFP-tagged mitochondrial proteins inside the vacuole and decreased free GFP, consistent with decreased mitophagy. Both PKC and high osmolarity glycerol (HOG) MAPK pathways were shown previously to be required for mitophagy. Activation of both MAPKs was defective in CL-deficient cells. Deletion of HOG pathway genes SHO1, SSK1, STE50, and HOG1 exacerbated crd1Δ growth. 1 m sorbitol and 0.2 m NaCl, which induce the HOG pathway, rescued growth of the mutant. Activation of the MAPK Slt2p was defective in crd1Δ cells, and up-regulation of the PKC pathway by expression of the PKC1R398P gene, which encodes constitutively activated Pkc1p, rescued crd1Δ growth and mitophagy defects. These findings indicate that loss of CL impairs MAPK pathway activation, and decreased activation of the PKC pathway leads to defective mitophagy.
Abeliovich, H. ; Dengjel, J. Mitophagy as a stress response in mammalian cells and in respiring S. cerevisiae. Biochemical Society Transactionsbiochemsoctrans 2016, 44, 541 - 545. Publisher's VersionAbstract
The degradation of malfunctioning or superfluous mitochondria in the lysosome/vacuole is an important housekeeping function in respiring eukaryotic cells. This clearance is thought to occur by a specific form of autophagic degradation called mitophagy, and plays a role in physiological homoeostasis as well as in the progression of late-onset diseases. Although the mechanism of bulk degradation by macroautophagy is relatively well established, the selective autophagic degradation of mitochondria has only recently begun to receive significant attention. In this mini-review, we introduce mitophagy as a form of mitochondrial quality control and proceed to provide specific examples from yeast and mammalian systems. We then discuss the relationship of mitophagy to mitochondrial stress, and provide a broad mechanistic overview of the process with an emphasis on evolutionarily conserved pathways.
Abeliovich, H. On Hill coefficients and subunit interaction energies. 2016, 73, 1399 - 1411. Publisher's VersionAbstract
The study of cooperative ligand binding to multimeric proteins aims to explain complex cooperative binding phenomena using concepts derived from ideal binding isotherms. The purpose of such efforts is the dissection of the cooperative binding isotherm into its interacting components, a result with a clear mechanistic value. Historically, cooperative binding is usually quantified using the Hill coefficient, $$\hbox {n}_\mathrm{H}$$nH, defined as the slope of the Hill plot at 50 % saturation. It was previously shown that the slope of the Hill plot throughout the titration is equal to the ratio of the binding variance in the system under study, to the binding variance of a reference non-interacting system. In the present contribution, this leads to a broader approach towards quantifying cooperativity, which empirically links cooperativity to the ensemble average of the subunit interaction energy. The resulting equations can be used to derive average differential subunit interaction energies directly from experimental binding isotherms. Combined with recent experimental advances in assessing binding distributions in multimeric proteins, these equations can also be used to calculate individual subunit interaction energies for specific n-ligated protein species.