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Summary

A plethora of cellular processes, including apoptosis, depend on regulated changes in mitochondrial shape and ultrastructure. Scarce is our understanding of the role of mitochondria and of their morphology during autophagy, a bulk degradation and recycling process of eukaryotic cells’ constituents. Here we show that mitochondrial morphology determines the cellular response to macroautophagy. When autophagy is triggered, mitochondria elongate in vitro and in vivo. Upon starvation cellular cAMP levels increase and protein kinase A (PKA) becomes activated. PKA in turn phosphorylates the pro-fission dynamin related protein 1 (DRP1) that is therefore retained in the cytoplasm, leading to unopposed mitochondrial fusion. Elongated mitochondria are spared from autophagic degradation, possess more cristae, increase dimerization and activity of ATP synthase, and maintain ATP production. When elongation is genetically or pharmacologically blocked, mitochondria conversely consume ATP, precipitating starvation-induced death. Thus, regulated changes in mitochondrial morphology determine the fate of the cell during autophagy.

Starvation induces a protective process of self-cannibalization called autophagy that is thought to mediate nonselective degradation of cytoplasmic material. We recently reported that mitochondria escape autophagosomal degradation through extensive fusion into mitochondrial networks upon certain starvation conditions. The extent of mitochondrial elongation is dependent on the type of nutrient deprivation, with amino acid depletion having a particularly strong effect. Downregulation of the mitochondrial fission protein Drp1 was determined to be important in bringing about starvation-induced mitochondrial fusion. The formation of mitochondrial networks during nutrient depletion selectively blocked their autophagic degradation, presumably allowing cells to sustain efficient ATP production and thereby survive starvation.

Macroautophagy is a cellular catabolic process that involves the sequestration of cytoplasmic constituents into double-membrane vesicles known as autophagosomes, which subsequently fuse with lysosomes, where they deliver their cargo for degradation. The main physiological role of autophagy is to recycle intracellular components, under conditions of nutrient deprivation, so as to supply cells with vital materials and energy. Selective autophagy also takes place in nutrient-rich conditions to rid the cell of damaged organelles or protein aggregates that would otherwise compromise cell viability. Mitophagy is a selective type of autophagy, whereby damaged or superfluous mitochondria are eliminated to maintain proper mitochondrial numbers and quality control. While mitophagy shares key regulatory factors with the general macroautophagy pathway, it also involves distinct steps, specific for mitochondrial elimination. Recent findings indicate that parkin and the phosphatase and tensin homolog-induced putative kinase protein 1 (PINK1), which have been implicated in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease, also regulate mitophagy and function to maintain mitochondrial homeostasis. Here, we survey the molecular mechanisms that govern the process of mitophagy and discuss its involvement in the onset and progression of neurodegenerative diseases during aging.

Macroautophagy (hereafter, autophagy) plays a critical role in maintaining cellular homeostasis by degrading protein aggregates and dysfunctional/damaged organelles. We recently reported that silencing the recessive familial Parkinson disease gene encoding PTEN-induced kinase 1 (PINK1) leads to neuronal cell death accompanied by mitochondrial dysfunction and Drp1-dependent fragmentation. In this model, mitochondrial fission and Beclin 1-dependent autophagy play protective roles, cooperating to sequester and eliminate damaged mitochondria. We discuss the role of superoxide and other reactive oxygen species upstream of mitochondrial depolarization, fission and autophagy in PINK1 knockdown lines. PINK1 deficiency appears to trigger several compensatory responses that together facilitate clearance of depolarized mitochondria, through a mechanism that is further enhanced by increased expression of parkin. These data offer additional insights that broaden the spectrum of potential interactions between PINK1 and parkin with respect to the regulation of mitochondrial homeostasis and mitophagy.

Macroautophagy is a cellular process by which cytosolic components and organelles are degraded in double-membrane bound structures upon fusion with lysosomes. A pathway for selective degradation of mitochondria by autophagy, known as mitophagy, has been described, and is of particular importance to neurons, because of the constant need for high levels of energy production in this cell type. Although much remains to be learned about mitophagy, it appears that the regulation of mitophagy shares key steps with the macroautophagy pathway, while exhibiting distinct regulatory steps specific for mitochondrial autophagic turnover. Mitophagy is emerging as an important pathway in neurodegenerative disease, and has been linked to the pathogenesis of Parkinson’s disease through the study of recessively inherited forms of this disorder, involving PINK1 and Parkin. Recent work indicates that PINK1 and Parkin together maintain mitochondrial quality control by regulating mitophagy. In the Purkinje cell degeneration (pcd) mouse, altered mitophagy may contribute to the dramatic neuron cell death observed in the cerebellum, suggesting that over-active mitophagy or insufficient mitophagy can both be deleterious. Finally, mitophagy has been linked to aging, as impaired macroautophagy over time promotes mitochondrial dysfunction associated with the aging process. Understanding the role of mitophagy in neural function, neurodegenerative disease, and aging represents an essential goal for future research in the autophagy field.

Macroautophagy (autophagy) is a lysosomal degradation pathway for the breakdown of intracellular proteins and organelles. Although, constitutive autophagy is a homeostatic mechanism for intracellular recycling and metabolic regulation, autophagy is also stress responsive where it is important for the removal of damaged proteins and organelles. Autophagy thereby confers stress tolerance, limits damage and sustains viability under adverse conditions. Autophagy is a tumor suppression mechanism yet it enables tumor cell survival in stress. Reconciling how loss of a prosurvival function can promote tumorigenesis, emerging evidence suggests that preservation of cellular fitness by autophagy may be key to tumor suppression. As autophagy is such a fundamental process, establishing how the functional status of autophagy influences tumorigenesis and treatment response is important. This is especially critical as many current cancer therapeutics activate autophagy. Therefore, efforts to understand and modulate the autophagy pathway will provide new approaches to cancer therapy and prevention.

Oligomerization of F1Fo-ATP synthase in the inner mitochondrial membrane governs the formation of cristae membrane domains. We show that the F1Fo-subunits Su i and Su k are crucial for the formation and maturation of ATP synthase dimers and oligomers. Su i additionally facilitates the incorporation of new subunits into ATP synthase monomers.

F1Fo-ATP synthase is a key enzyme of oxidative phosphorylation that is localized in the inner membrane of mitochondria. It uses the energy stored in the proton gradient across the inner mitochondrial membrane to catalyze the synthesis of ATP from ADP and phosphate. Dimeric and higher oligomeric forms of ATP synthase have been observed in mitochondria from various organisms. Oligomerization of ATP synthase is critical for the morphology of the inner mitochondrial membrane because it supports the generation of tubular cristae membrane domains. Association of individual F1Fo-ATP synthase complexes is mediated by the membrane-embedded Fo-part. Several subunits were mapped to monomer-monomer-interfaces of yeast ATP synthase complexes, but only Su e (Atp21) and Su g (Atp20) have so far been identified as crucial for the formation of stable dimers. We show that two other small Fo-components, Su k (Atp19) and Su i (Atp18) are involved in the stepwise assembly of F1Fo-ATP synthase dimers and oligomers. We have identified an intermediate form of the ATP synthase dimer, which accumulates in the absence of Su i. Moreover, our data indicate that Su i facilitates the incorporation of newly synthesized subunits into ATP synthase complexes.

Macroautophagy has been implicated as a mechanism of cell death. However, the relationship between this degradative pathway and cell death is unclear as macroautophagy has been shown recently to protect against apoptosis. To better define the inter-play between these two critical cellular processes, we determined whether inhibition of macroautophagy could have both pro-apoptotic and anti-apoptotic effects in the same cell. Embryonic fibroblasts from mice with a knock-out of the essential macroautophagy gene atg5 were treated with activators of the extrinsic and intrinsic death pathways. Loss of macroautophagy sensitized these cells to caspase-dependent apoptosis from the death receptor ligands Fas and tumor necrosis factor-α (TNF-α). Atg5−/− mouse embryonic fibroblasts had increased activation of the mitochondrial death pathway in response to Fas/TNF-α in concert with decreased ATP levels. Fas/TNF-α treatment failed to up-regulate macroautophagy, and in fact, decreased activity at late time points. In contrast to their sensitization to Fas/TNF-α, Atg5−/− cells were resistant to death from menadione and UV light. In the absence of macroautophagy, an up-regulation of chaperone-mediated autophagy induced resistance to these stressors. These results demonstrate that inhibition of macroautophagy can promote or prevent apoptosis in the same cell and that the response is governed by the nature of the death stimulus and compensatory changes in other forms of autophagy. Experimental findings that an inhibition of macroautophagy blocks apoptosis do not prove that autophagy mediates cell death as this effect may result from the protective up-regulation of other autophagic pathways such as chaperone-mediated autophagy.

Protein aggregation, mitochondrial impairment and oxidative stress are common to multiple neurodegenerative diseases. Homeostasis is regulated by a balanced set of anabolic and catabolic responses, which govern removal and repair of damaged proteins and organelles. Macroautophagy is an evolutionarily conserved pathway for the degradation of long-lived proteins, effete organelles and protein aggregates. Aberrations in macroautophagy have been observed in Alzheimer, Huntington, Parkinson, motor neurone and prion diseases. In this review, we will discuss the divergent roles of macroautophagy in neuro-degenerative diseases and suggest a potential regulatory mechanism that could determine cell death or survival outcomes. We also highlight emerging data on neurite morphology and synaptic remodelling that indicate the possibility of detrimental functional trade-offs in the face of neuronal cell survival, particularly if the need for elevated macroautophagy is sustained.

Mitochondria are complex organelles with a highly dynamic distribution and internal organization. Here, we demonstrate that mitofilin, a previously identified mitochondrial protein of unknown function, controls mitochondrial cristae morphology. Mitofilin is enriched in the narrow space between the inner boundary and the outer membranes, where it forms a homotypic interaction and assembles into a large multimeric protein complex. Down-regulation of mitofilin in HeLa cells by using specific small interfering RNA lead to decreased cellular proliferation and increased apoptosis, suggesting abnormal mitochondrial function. Although gross mitochondrial fission and fusion seemed normal, ultrastructural studies revealed disorganized mitochondrial inner membrane. Inner membranes failed to form tubular or vesicular cristae and showed as closely packed stacks of membrane sheets that fused intermittently, resulting in a complex maze of membranous network. Electron microscopic tomography estimated a substantial increase in inner:outer membrane ratio, whereas no cristae junctions were detected. In addition, mitochondria subsequently exhibited increased reactive oxygen species production and membrane potential. Although metabolic flux increased due to mitofilin deficiency, mitochondrial oxidative phosphorylation was not increased accordingly. We propose that mitofilin is a critical organizer of the mitochondrial cristae morphology and thus indispensable for normal mitochondrial function.

Mitochondrial distribution and morphology depend on MDM33, a Saccharomyces cerevisiae gene encoding a novel protein of the mitochondrial inner membrane. Cells lacking Mdm33 contain ring-shaped, mostly interconnected mitochondria, which are able to form large hollow spheres. On the ultrastructural level, these aberrant organelles display extremely elongated stretches of outer and inner membranes enclosing a very narrow matrix space. Dilated parts of Δmdm33 mitochondria contain well-developed cristae. Overexpression of Mdm33 leads to growth arrest, aggregation of mitochondria, and generation of aberrant inner membrane structures, including septa, inner membrane fragments, and loss of inner membrane cristae. The MDM33 gene is required for the formation of net-like mitochondria in mutants lacking components of the outer membrane fission machinery, and mitochondrial fusion is required for the formation of extended ring-like mitochondria in cells lacking the MDM33 gene. The Mdm33 protein assembles into an oligomeric complex in the inner membrane where it performs homotypic protein–protein interactions. Our results indicate that Mdm33 plays a distinct role in the mitochondrial inner membrane to control mitochondrial morphology. We propose that Mdm33 is involved in fission of the mitochondrial inner membrane.

Mitochondria are dynamic and are able to interchange their morphology between elongated interconnected mitochondrial networks and a fragmented disconnected arrangement by the processes of mitochondrial fusion and fission, respectively. Changes in mitochondrial morphology are regulated by the mitochondrial fusion proteins (mitofusins 1 and 2, and optic atrophy 1) and the mitochondrial fission proteins (dynamin-related peptide 1 and mitochondrial fission protein 1) and have been implicated in a variety of biological processes including embryonic development, metabolism, apoptosis, and autophagy, although the majority of studies have been largely confined to non-cardiac cells. Despite the unique arrangement of mitochondria in the adult heart, emerging data suggest that changes in mitochondrial morphology may be relevant to various aspects of cardiovascular biology—these include cardiac development, the response to ischaemia–reperfusion injury, heart failure, diabetes mellitus, and apoptosis. Interestingly, the machinery required for altering mitochondrial shape in terms of the mitochondrial fusion and fission proteins are all present in the adult heart, but their physiological function remains unclear. In this article, we review the current developments in this exciting new field of mitochondrial biology, the implications for cardiovascular physiology, and the potential for discovering novel therapeutic strategies for treating cardiovascular disease.

Huntington's disease (HD), a genetic neurodegenerative disease caused by a polyglutamine expansion in the Huntingtin (Htt) protein, is accompanied by multiple mitochondrial alterations. Here we show that mitochondrial fragmentation and cristae alterations characterize cellular models of HD and participate in their increased susceptibility to apoptosis. In HD cells the increased basal activity of the phosphatase calcineurin dephosphorylates the pro-fission dynamin related protein 1 (Drp1), increasing its mitochondrial translocation and activation, and ultimately leading to fragmentation of the organelle. The fragmented HD mitochondria are characterized by cristae alterations that are aggravated by apoptotic stimulation. A genetic analysis indicates that correction of mitochondrial elongation is not sufficient to rescue the increased cytochrome c release and cell death observed in HD cells. Conversely, the increased apoptosis can be corrected by manoeuvres that prevent fission and cristae remodelling. In conclusion, the cristae remodelling of the fragmented HD mitochondria contributes to their hypersensitivity to apoptosis.

Huntington's disease (HD), a genetic neurodegenerative disease caused by a polyglutamine expansion in the Huntingtin (Htt) protein, is accompanied by multiple mitochondrial alterations. Here, we show that mitochondrial fragmentation and cristae alterations characterize cellular models of HD and participate in their increased susceptibility to apoptosis. In HD cells, the increased basal activity of the phosphatase calcineurin dephosphorylates the pro-fission dynamin related protein 1 (Drp1), increasing its mitochondrial translocation and activation, and ultimately leading to fragmentation of the organelle. The fragmented HD mitochondria are characterized by cristae alterations that are aggravated by apoptotic stimulation. A genetic analysis indicates that correction of mitochondrial elongation is not sufficient to rescue the increased cytochrome c release and cell death observed in HD cells. Conversely, the increased apoptosis can be corrected by manoeuvres that prevent fission and cristae remodelling. In conclusion, the cristae remodelling of the fragmented HD mitochondria contributes to their hypersensitivity to apoptosis.

Huntington's disease (HD), a genetic neurodegenerative disease caused by a polyglutamine expansion in the Huntingtin (Htt) protein, is accompanied by multiple mitochondrial alterations. Here, we show that mitochondrial fragmentation and cristae alterations characterize cellular models of HD and participate in their increased susceptibility to apoptosis. In HD cells, the increased basal activity of the phosphatase calcineurin dephosphorylates the pro-fission dynamin related protein 1 (Drp1), increasing its mitochondrial translocation and activation, and ultimately leading to fragmentation of the organelle. The fragmented HD mitochondria are characterized by cristae alterations that are aggravated by apoptotic stimulation. A genetic analysis indicates that correction of mitochondrial elongation is not sufficient to rescue the increased cytochrome c release and cell death observed in HD cells. Conversely, the increased apoptosis can be corrected by manoeuvres that prevent fission and cristae remodelling. In conclusion, the cristae remodelling of the fragmented HD mitochondria contributes to their hypersensitivity to apoptosis.

Mitochondrial quality control is important to maintain proper cellular homeostasis. Although selective mitochondrial degradation by autophagy (mitophagy) is suggested to have an important role for quality control and there is evidence for a direct relation between mitophagy and neurodegenerative diseases, the molecular mechanism of mitophagy is poorly understood. Using a screen for mitophagy-deficient mutants, we found that YIL146C/ECM37 is essential for mitophagy. This gene is not required for other types of selective autophagy or for nonspecific macroautophagy. We designated this autophagy-related (ATG) gene as ATG32. The Atg32 protein localizes on mitochondria. Following the induction of mitophagy, Atg32 binds Atg11, an adaptor protein for selective types of autophagy, and then Atg32 is recruited to and imported into the vacuole along with mitochondria. Therefore, Atg32 confers selectivity for mitochondrial sequestration as a cargo and is necessary for recruitment of this organelle by the autophagy machinery for mitophagy.

Mitochondria continuously change their shape and thereby influence different cellular processes like cell death or development. Recently, we showed that during starvation mitochondria fuse into a highly connected network. The change in mitochondrial shape was dependent on inactivation of the fission protein Drp1, through targeting of two different phosphorylation sites. This rapid inhibition of mitochondrial fission led to unopposed fusion, protecting mitochondria from starvation-induced degradation and enabling the cell to survive nutrient scarce conditions.

Macroautophagy (often referred to as autophagy) is an evolutionarily conserved intracellular system by which macromolecules and organelles are delivered to lysosomes for degradation and recycling. Autophagy is robustly induced in response to starvation in order to generate nutrients and energy through the lysosomal degradation of cytoplasmic components. Constitutive, basal autophagy serves as a quality control mechanism for the elimination of aggregated proteins and worn-out or damaged organelles, such as mitochondria. Research during the last decade has made it clear that malfunctioning or failure of this system is associated with a vide range of human pathologies and age-related diseases. Our recent data provide strong evidence for the role of autophagy in the pathogenesis of Pompe disease, a lysosomal glycogen storage disease caused by deficiency of acid alpha-glucosidase (GAA). Large pools of autophagic debris in skeletal muscle cells can be seen in both our GAA knockout model and patients with Pompe disease. In this review, we will focus on these recent data, and comment on the not so recent observations pointing to the involvement of autophagy in skeletal muscle damage in Pompe disease.

Summary

During human pregnancy, placental trophoblasts differentiate and syncytialize into syncytiotrophoblasts that sustain progesterone production [1]. This process is accompanied by mitochondrial fragmentation and cristae remodeling [2], two facets of mitochondrial apoptosis, whose molecular mechanisms and functional consequences on steroidogenesis are unclear. Here we show that the mitochondria-shaping protein Optic atrophy 1 (Opa1) controls efficiency of steroidogenesis. During syncytialization of trophoblast BeWo cells, levels of the profission mitochondria-shaping protein Drp1 increase, and those of Opa1 and mitofusin (Mfn) decrease, leading to mitochondrial fragmentation and cristae remodeling. Manipulation of the levels of Opa1 reveal an inverse relationship with the efficiency of steroidogenesis in trophoblasts and in mouse embryonic fibroblasts where the mitochondrial steroidogenetic pathway has been engineered. In an in vitro assay, accumulation of cholesterol is facilitated in the inner membrane of isolated mitochondria lacking Opa1. Thus, Opa1-dependent inner membrane remodeling controls efficiency of steroidogenesis.

Graphical Abstract

Highlights

► Mitochondrial remodeling characterize differentiation of human trophoblasts ► Expression of Opa1 decreases during trophoblast differentiation ► Lowered Opa1 increases efficiency of steroidogenesis stimulating cholesterol flux

Mitochondria are important organelles for providing the ATP and carbon skeletons required to sustain cell growth. While these organelles also participate in other key metabolic functions across species, they have a specialized role in plants of optimizing photosynthesis through participating in photorespiration. It is therefore critical to map the protein composition of mitochondria in plants to gain a better understanding of their regulation and define the uniqueness of their metabolic networks. To date, <30% of the predicted number of mitochondrial proteins has been verified experimentally by proteomics and/or GFP localization studies. In this mini-review, we will provide an overview of the advances in mitochondrial proteomics in the model plant Arabidopsis thaliana over the past 5 years. The ultimate goal of mapping the mitochondrial proteome in Arabidopsis is to discover novel mitochondrial components that are critical during development in plants as well as genes involved in developmental abnormalities, such as those implicated in mitochondrial-linked cytoplasmic male sterility.

Sustained hypertension promotes structural, functional and metabolic remodeling of cardiomyocyte mitochondria. As long-lived, postmitotic cells, cardiomyocytes turn over mitochondria continuously to compensate for changes in energy demands and to remove damaged organelles. This process involves fusion and fission of existing mitochondria to generate new organelles and separate old ones for degradation via autophagy. Autophagy is a lysosome-dependent proteolytic pathway capable of processing cellular components, including organelles and protein aggregates. Autophagy can be either nonselective or selective and contributes to remodeling of the myocardium under stress. Fission of mitochondria, loss of membrane potential, and ubiquitination are emerging as critical steps that direct selective autophagic degradation of mitochondria. This review discusses the molecular mechanisms controlling mitochondrial dynamics, including fission, fusion, transport, and degradation. Furthermore, it examines recent studies revealing the importance of these processes in normal and diseased heart.

Macroautophagy (hereafter autophagy) is a ubiquitous degradative process in eukaryotic cells.1 Mitochondria autophagy (mitophagy) is a type of specific autophagy that degrades mitochondria selectively.2 Mitophagy is thought to play an important role for maintaining the quality of these organelles by eliminating damaged mitochondria, and it is involved in cellular differentiation, whereas dysfunctional mitophagy is related with neurodegenerative diseases;3-5 however, the mechanism of mitophagy is poorly understood. To facilitate the analysis of mitophagy, we recently established a simple method to monitor mitophagy in yeast, the Om45-GFP processing assay.6 Om45-GFP is a mitochondrial outer membrane protein. Following the uptake of mitochondria into the vacuole, Om45-GFP is degraded, releasing the intact form of GFP, which is detected by immunoblotting. Therefore, the amount of free GFP reflects the level of mitophagy.

The MAP kinase Slt2 is required for both mitophagy and pexophagy, whereas the MAP kinase Hog1 acts specifically in mitophagy.

Macroautophagy (hereafter referred to simply as autophagy) is a catabolic pathway that mediates the degradation of long-lived proteins and organelles in eukaryotic cells. The regulation of mitochondrial degradation through autophagy plays an essential role in the maintenance and quality control of this organelle. Compared with our understanding of the essential function of mitochondria in many aspects of cellular metabolism such as energy production and of the role of dysfunctional mitochondria in cell death, little is known regarding their degradation and especially how upstream signaling pathways control this process. Here, we report that two mitogen-activated protein kinases (MAPKs), Slt2 and Hog1, are required for mitophagy in Saccharomyces cerevisiae. Slt2 is required for the degradation of both mitochondria and peroxisomes (via pexophagy), whereas Hog1 functions specifically in mitophagy. Slt2 also affects the recruitment of mitochondria to the phagophore assembly site (PAS), a critical step in the packaging of cargo for selective degradation.

The accumulation of unhealthy mitochondria results in mitochondrial dysfunction, which has been implicated in aging, cancer, and a variety of degenerative diseases. However, the mechanism by which mitochondrial quality is regulated remains unclear. Here, we show that Mieap, a novel p53-inducible protein, induces intramitochondrial lysosome-like organella that plays a critical role in mitochondrial quality control. Mieap expression is directly regulated by p53 and is frequently lost in human cancer as result of DNA methylation. Mieap dramatically induces the accumulation of lysosomal proteins within mitochondria and mitochondrial acidic condition without destroying the mitochondrial structure (designated MALM, for Mieap-induced accumulation of lysosome-like organelles within mitochondria) in response to mitochondrial damage. MALM was not related to canonical autophagy. MALM is involved in the degradation of oxidized mitochondrial proteins, leading to increased ATP synthesis and decreased reactive oxygen species generation. These results suggest that Mieap induces intramitochondrial lysosome-like organella that plays a critical role in mitochondrial quality control by eliminating oxidized mitochondrial proteins. Cancer cells might accumulate unhealthy mitochondria due to p53 mutations and/or Mieap methylation, representing a potential cause of the Warburg effect.

Autophagy is the process by which organelles and portions of the cytoplasm are degraded in lysosomes. Several different forms of autophagy are known that are distinguishable chiefly by the mode in which cargo is delivered to the lysosome for degradation. Ubiquilin was recently reported to regulate macroautophagy, the form of autophagy in which cytosolic cargo is packaged in a double-membrane structure or autophagosome that fuses with lysosomes for degradation. We confirm here using different morphological and biochemical procedures that ubiquilin is present in autophagosomes in HeLa cells and in brain and liver tissue of mouse. Coimmunoprecipitation studies indicated that ubiquilin binds the autophagosome marker LC3 in a complex and that reduction of ubiquilin expression reduces autophagosome formation, which correlates with a reduction in maturation of LC3-I to the LC3-II form of the protein. We found that ubiquilin is degraded during both macroautophagy and during chaperone-mediated autophagy (CMA), the latter of which involves the active transport of proteins into lysosomes. We discuss the implication of this degradation in mediating cross-talk between macroautophagy and CMA. Finally, we demonstrate that ubiquilin protects cells against starvation-induced cell death propagated by overexpression of mutant Alzheimer's disease PS2N141I protein and green fluorescent protein (GFP)-huntingtin exon-1 fusion protein containing 74 polyglutamines.