The peroxisomal Lon protease LonP2 in aging and disease: functions and comparisons with mitochondrial Lon protease LonP1

Peroxisomes are ubiquitous eukaryotic organelles with the primary role of breaking down very long‐ and branched‐chain fatty acids for subsequent β‐oxidation in the mitochondrion. Like mitochondria, peroxisomes are major sites for oxygen utilization and potential contributors to cellular oxidative stress. The accumulation of oxidatively damaged proteins, which often develop into inclusion bodies (of oxidized, aggregated, and cross‐linked proteins) within both mitochondria and peroxisomes, results in loss of organelle function that may contribute to the aging process. Both organelles possess an isoform of the Lon protease that is responsible for degrading proteins damaged by oxidation. While the importance of mitochondrial Lon (LonP1) in relation to oxidative stress and aging has been established, little is known regarding the role of LonP2 and aging‐related changes in the peroxisome. Recently, peroxisome dysfunction has been associated with aging‐related diseases indicating that peroxisome maintenance is a critical component of ‘healthy aging’. Although mitochondria and peroxisomes are both needed for fatty acid metabolism, little work has focused on understanding the relationship between these two organelles including how age‐dependent changes in one organelle may be detrimental for the other. Herein, we summarize findings that establish proteolytic degradation of damaged proteins by the Lon protease as a vital mechanism to maintain protein homeostasis within the peroxisome. Due to the metabolic coordination between peroxisomes and mitochondria, understanding the role of Lon in the aging peroxisome may help to elucidate cellular causes for both peroxisome and mitochondrial dysfunction.     

Building the mitochondrial proteome

Mitochondria are essential organelles for cellular homeostasis. A variety of pathologies including cancer, myopathies, diabetes, obesity, aging and neurodegenerative diseases are linked to mitochondrial dysfunction. Therefore, mapping the different components of mitochondria is of particular interest to gain further understanding of such diseases. In recent years, proteomics-based approaches have been developed in attempts to determine the complete set of mitochondrial proteins in yeast, plants and mammals. In addition, proteomics-based methods have been applied not only to the analysis of protein function in the organelle, but also to identify biomarkers for diagnosis and therapeutic targets of specific pathologies associated with mitochondria. Altogether, it is becoming clear that proteomics is a powerful tool not only to identify currently unknown components of the mitochondrion, but also to study the different roles of the organelle in cellular homeostasis.     

Building the mitochondrial proteome

Mitochondria are essential organelles for cellular homeostasis. A variety of pathologies including cancer, myopathies, diabetes, obesity, aging and neurodegenerative diseases are linked to mitochondrial dysfunction. Therefore, mapping the different components of mitochondria is of particular interest to gain further understanding of such diseases. In recent years, proteomics-based approaches have been developed in attempts to determine the complete set of mitochondrial proteins in yeast, plants and mammals. In addition, proteomics-based methods have been applied not only to the analysis of protein function in the organelle, but also to identify biomarkers for diagnosis and therapeutic targets of specific pathologies associated with mitochondria. Altogether, it is becoming clear that proteomics is a powerful tool not only to identify currently unknown components of the mitochondrion, but also to study the different roles of the organelle in cellular homeostasis.     

The vacuolar shapes of ageing: From function to morphology

Cellular ageing results in accumulating damage to various macromolecules and the progressive decline of organelle function. Yeast vacuoles as well as their counterpart in higher eukaryotes, the lysosomes, emerge as central organelles in lifespan determination. These acidic organelles integrate enzymatic breakdown and recycling of cellular waste with nutrient sensing, storage, signalling and mobilization. Establishing physical contact with virtually all other organelles, vacuoles serve as hubs of cellular homeostasis. Studies in Saccharomyces cerevisiae contributed substantially to our understanding of the ageing process per se and the multifaceted roles of vacuoles/lysosomes in the maintenance of cellular fitness with progressing age. Here, we discuss the multiple roles of the vacuole during ageing, ranging from vacuolar dynamics and acidification as determinants of lifespan to the function of this organelle as waste bin, recycling facility, nutrient reservoir and integrator of nutrient signalling.     

Eating the endoplasmic reticulum: quality control by autophagy

Autophagy is connected to a surprising range of cellular processes, including the stress response, developmental remodeling, organelle homeostasis and disease pathophysiology. The inducible, predominant form of autophagy, macroautophagy, involves dynamic membrane rearrangements, culminating in the formation of a double-membrane cytosolic vesicle, an autophagosome, which sequesters cytoplasm and organelles. The signal transduction mechanisms that regulate autophagy are poorly understood and have focused on extracellular nutrient sensing. Similarly, little is known about the contribution of the endomembrane organelles to autophagy-related processes. Recent studies have provided interesting links between these topics, revealing that the secretory pathway provides membrane for autophagosome formation, and that autophagy has an important role in organelle homeostasis.     

Cross‐compartment proteostasis regulation during redox imbalance induced ER stress

Imbalance in protein homeostasis in specific subcellular organelles is alleviated through organelle‐specific stress response pathways. As a canonical example of stress activated pathway, accumulation of misfolded proteins in ER activates unfolded protein response (UPR) in almost all eukaryotic organisms. However, very little is known about the involvement of proteins of other organelles that help to maintain the cellular protein homeostasis during ER stress. In this study, using iTRAQ‐based LC–MS approach, we identified organelle enriched proteins that are differentially expressed in yeast (Saccharomyces cerevisiae) during ER stress in the absence of UPR sensor Ire1p. We have identified about 750 proteins from enriched organelle fraction in three independent iTRAQ experiments. Induction of ER stress resulted in the differential expression of 93 proteins in WT strains, 40 of which were found to be dependent on IRE1. Our study reveals a cross‐talk between ER‐ and mitochondrial proteostasis exemplified by an Ire1p‐dependent induction of Hsp60p, a mitochondrial chaperone. Thus, in this study, we show changes in protein levels in various organelles in response to ER stress. A large fraction of these changes were dependent on canonical UPR signalling through Ire1, highlighting the importance of interorganellar cross‐talk during stress.     

Organelle communication: Signaling crossroads between homeostasis and disease

Cellular organelles do not function as isolated or static units, but rather form dynamic contacts between one another that can be modulated according to cellular needs. The physical interfaces between organelles are important for Ca²⁺ and lipid homeostasis, and serve as platforms for the control of many essential functions including metabolism, signaling, organelle integrity and execution of the apoptotic program. Emerging evidence also highlights the importance of organelle communication in disorders such as Alzheimer's disease, pulmonary arterial hypertension, cancer, skeletal and cardiac muscle dysfunction. Here, we provide an overview of the current literature on organelle communication and the link to human pathologies.     

Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice

Studies on cell division traditionally focus on the mechanisms of chromosome segregation and cytokinesis, yet we know comparatively little about how organelles segregate. Analysis of organelle partitioning in asymmetrically dividing cells has provided insights into the mechanisms through which cells control organelle distribution. Interestingly, these studies have revealed that segregation mechanisms frequently link organelle distribution to organelle growth and formation. Furthermore, in many cases, cells use organelles, such as the endoplasmic reticulum and P granules, as vectors for the segregation of information. Together, these emerging data suggest that the coordination between organelle growth, division, and segregation plays an important role in the control of cell fate inheritance, cellular aging, and rejuvenation, i.e., the resetting of age in immortal lineages.     

Peroxisomes, cell senescence, and rates of aging

The peroxisome is functionally integrated into an exquisitely complex network of communicating endomembranes which is only beginning to be appreciated. Despite great advances in identifying essential components and characterizing molecular mechanisms associated with the organelle's biogenesis and function, there is a large gap in our understanding of how peroxisomes are incorporated into metabolic pathways and subcellular communication networks, how they contribute to cellular aging, and where their influence is manifested on the initiation and progression of degenerative disease. In this review, we summarize recent evidence pointing to the organelle as an important regulator of cellular redox balance with potentially far-reaching effects on cell aging and the genesis of human disease. The roles of the organelle in lipid homeostasis, anaplerotic reactions, and other critical metabolic and biochemical processes are addressed elsewhere in this volume. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease.     

Mitochondria and endoplasmic reticulum: mitochondria-endoplasmic reticulum interplay in type 2 diabetes pathophysiology

Mitochondria and endoplasmic reticulum (ER) are two important metabolic organelles for the maintenance of cellular homeostasis and their functional defects are suspected to participate to the aetiology of type 2 diabetes (T2D). Particularly, excessive lipid intake and/or ectopic lipid accumulation in tissues (referred as lipotoxicity) are involved in alterations of both organelles and are closely linked to peripheral insulin resistance and defective insulin secretion. Since, mitochondria and ER are physically and functionally interconnected, their respective alterations during T2D could be interrelated. However, the mechanisms that coordinate the interplay between mitochondrial dysfunction and ER stress, and its relevance in the control of glucose homeostasis are unknown. Among these mechanisms, we will discuss on the potential role of altered mitochondria/ER crosstalk in organelle dysfunctions and in T2D pathophysiology.     

Development of the endoplasmic reticulum, mitochondrion and apicoplast during the asexual life cycle of Plasmodium falciparum

Plasmodium parasites are unicellular eukaryotes that undergo a series of remarkable morphological transformations during the course of a multistage life cycle spanning two hosts (mosquito and human). Relatively little is known about the dynamics of cellular organelles throughout the course of these transformations. Here we describe the morphology of three organelles (endoplasmic reticulum, apicoplast and mitochondrion) through the human blood stages of the parasite life cycle using fluorescent reporter proteins fused to organelle targeting sequences. The endoplasmic reticulum begins as a simple crescent-shaped organelle that develops into a perinuclear ring with two small protrusions, followed by transformation into an extensive reticulated network as the parasite enlarges. Similarly, the apicoplast and the mitochondrion grow from single, small, discrete organelles into highly branched structures in later-stage parasites. These branched structures undergo an ordered fission - apicoplast followed by mitochondrion - to create multiple daughter organelles that are apparently linked as pairs for packaging into daughter cells. This is the first in-depth examination of intracellular organelles in live parasites during the asexual life cycle of this important human pathogen.     

Autophagy in stem cell aging

Aging is responsible for changes in mammalian tissues that result in an imbalance to tissue homeostasis and a decline in the regeneration capacity of organs due to stem cell exhaustion. Autophagy is a constitutive pathway necessary to degrade damaged organelles and protein aggregates. Autophagy is one of the hallmarks of aging, which involves a decline in the number and functionality of stem cells. Recent studies show that stem cells require autophagy to get rid of cellular waste produced during the quiescent stage. In particular, two independent studies in muscle and hematopoietic stem cells demonstrate the relevance of the autophagy impairment for stem cell exhaustion and aging. In this review, we summarize the main results of these works, which helped to elucidate the impact of autophagy in stem cell activity as well as in age‐associated diseases.     

Mitochondria as a target of cardioprotection in models of preconditioning

Over the recent years the view on mitochondria in the heart as a cellular powerhouse providing ATP supply needed to sustain contractile function, basal metabolic processes, and ionic homeostasis has changed radically. At present it is known that dysfunctions of these organelles are essential in the development of a large number of diseases, including cardiovascular diseases. Moreover, mitochondria are considered to be a very promising target of endogenous strategies that are essential in the protection of the myocardium from acute ischemia/reperfusion injury. These strategies including ischemic preconditioning, remote ischemic preconditioning as well as the acute phase of streptozotocin-induced diabetes mellitus, provide a similar effect of protection. Alterations observed in the functional and structural properties of heart mitochondria caused by short-term pathological impulses are associated with endogenous cardioprotective processes. It seems that the extent of mitochondrial membrane fluidization could be an active response mechanism to injury with a subtle effect on membrane-associated processes which further affect the environment of the whole organelle, thus inducing metabolic changes in the heart. In this review article, we provide an overview of endogenous protective mechanisms induced by hypoxic, pseudohypoxic and ischemic conditions with special consideration of the role of heart mitochondria in these processes.     

Mutations that disrupt the morphogenesis and localization of a sperm-specific organelle in Caenorhabditis elegans

Nematode sperm contain unusual organelles, membranous organelles, which undergo dramatic morphological changes during spermatogenesis. Early in spermatogenesis, the membranous organelle functions to transport sperm specific components to the spermatids; later, during the formation of the crawling spermatozoa, it adds new components to the cell surface as it fuses with the plasma membrane. Genetic analysis of spermatogenesis in the nematode Caenorhabditis elegans has revealed mutations that specifically disrupt the proper cellular localization and morphogenesis of this organelle. In animals homozygous for the either the known deficiency hcDf1 or the probable deficiency h12, the membranes of the membranous organelles are aberrantly covered with ribosomes. A mutation in the spermatogenesis-defective spe-10 gene causes severe defects in the morphogenesis of a fibrous body-membranous organelle complex. In both cases, these mutations also disrupt the proper localization of both nuclei and membranous organelles in haploid spermatids and spermatozoa.     

Keeping zombies alive: The ER-mitochondria Ca2+ transfer in cellular senescence

Cellular senescence generates a permanent cell cycle arrest, characterized by apoptosis resistance and a pro-inflammatory senescence-associated secretory phenotype (SASP). Physiologically, senescent cells promote tissue remodeling during development and after injury. However, when accumulated over a certain threshold as happens during aging or after cellular stress, senescent cells contribute to the functional decline of tissues, participating in the generation of several diseases. Cellular senescence is accompanied by increased mitochondrial metabolism. How mitochondrial function is regulated and what role it plays in senescent cell homeostasis is poorly understood. Mitochondria are functionally and physically coupled to the endoplasmic reticulum (ER), the major calcium (Ca²⁺) storage organelle in mammalian cells, through special domains known as mitochondria-ER contacts (MERCs). In this domain, the release of Ca²⁺ from the ER is mainly regulated by inositol 1,4,5-trisphosphate receptors (IP3Rs), a family of three Ca²⁺ release channels activated by a ligand (IP3). IP3R-mediated Ca²⁺ release is transferred to mitochondria through the mitochondrial Ca²⁺ uniporter (MCU), where it modulates the activity of several enzymes and transporters impacting its bioenergetic and biosynthetic function. Here, we review the possible connection between ER to mitochondria Ca²⁺ transfer and senescence.Understanding the pathways that contribute to senescence is essential to reveal new therapeutic targets that allow either delaying senescent cell accumulation or reduce senescent cell burden to alleviate multiple diseases.     

Mitochondrial protein quality control during biogenesis and aging

Mitochondrial dysfunction has long been associated with the aging process and the onset of numerous diseases. Regulation of the complex protein-folding environment within the organelle is essential for maintaining efficient metabolic output. Over time, dysregulation of protein homeostasis arises through stress induced by the accumulation of reactive oxygen species and mutations in the mitochondrial genome introduced during replication. To preserve organelle function during biogenesis, remodeling and stress, quality control of mitochondrial proteins must be monitored by molecular chaperones and proteases stationed in the four compartments of the organelle. Here, we review mitochondrial protein quality control with a focus on organelle biogenesis and aging.     

Association of kinesin with characterized membrane-bounded organelles.

The family of molecular motors known as kinesin has been implicated in the translocation of membrane-bounded organelles along microtubules, but relatively little is known about the interaction of kinesin with organelles. In order to understand these interactions, we have examined the association of kinesin with a variety of organelles. Kinesin was detected in purified organelle fractions, including synaptic vesicles, mitochondria, and coated vesicles, using quantitative immunoblots and immunoelectron microscopy. In contrast, isolated Golgi membranes and nuclear fractions did not contain detectable levels of kinesin. These results demonstrate that the organelle binding capacity of kinesin is selective and specific. The ability to purify membrane-bounded organelles with associated kinesin indicates that at least a portion of the cellular kinesin has a relatively stable association with membrane-bounded organelles in the cell. In addition, immunoelectron microscopy of mitochondria revealed a patch-like pattern in the kinesin distribution, suggesting that the organization of the motor on the organelle membrane may play a role in regulating organelle motility.     

Mechanisms of Organelle Inheritance in Dividing Plant Cells

Organelles form essential compartments of all eukaryotic cells. Mechanisms that ensure the unbiased inheritance of organelles during cell division are therefore necessary to maintain the viability of future cell generations. Although inheritance of organelles represents a fundamental component of the cell cycle, surprisingly little is known about the underlying mechanisms that facilitate unbiased organelle inheritance. Evidence from a select number of studies, however, indicates that ordered organelle inheritance strategies exist in dividing cells of higher plants. The basic requirement for unbiased organelle inheritance is the duplication of organelle volume and distribution of the resulting organelle populations in a manner that facilitates unbiased partitioning of the organelle population to each daughter cell. Often, partitioning strategies are specific to the organelle, being influenced by the functional requirements of the organelle and whether the cells are mitotically active or re-entering into the cell cycle. Organelle partitioning mechanisms frequently depend on interactions with either the actin or microtubule cytoskeleton. In this focused review, we attempt to summarize key findings regarding organelle partitioning strategies in dividing cells of higher plants. We particularly concentrate on the role of the cytoskeleton in mediating unbiased organelle partitioning.     

溶酶体途径在细胞自噬过程中的功能意义

溶酶体具有高度保守的异质性,是细胞自噬的关键细胞器。细胞质中的蛋白质和细胞器最终在溶酶体降解,故溶酶体在维持细胞结构和功能的平衡方面起着重要生理作用。通过自噬溶酶体途径,细胞可清除某些病原体并参与抗原呈递。细胞自噬与异噬经溶酶体密切联系。自噬过程中溶酶体功能障碍与某些疾病和衰老等相关。对细胞自噬的溶酶体途径及其功能意义作了概述。