scholarly journals Skeletal Phenotypes Due to Abnormalities in Mitochondrial Protein Homeostasis and Import

2020 ◽  
Vol 21 (21) ◽  
pp. 8327
Author(s):  
Tian Zhao ◽  
Caitlin Goedhart ◽  
Gerald Pfeffer ◽  
Steven C Greenway ◽  
Matthew Lines ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Disease ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Membrane Lipid ◽  
Disease Genes ◽  
Protein Homeostasis ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Functions ◽  
Insight Into

Mitochondrial disease represents a collection of rare genetic disorders caused by mitochondrial dysfunction. These disorders can be quite complex and heterogeneous, and it is recognized that mitochondrial disease can affect any tissue at any age. The reasons for this variability are not well understood. In this review, we develop and expand a subset of mitochondrial diseases including predominantly skeletal phenotypes. Understanding how impairment ofdiverse mitochondrial functions leads to a skeletal phenotype will help diagnose and treat patients with mitochondrial disease and provide additional insight into the growing list of human pathologies associated with mitochondrial dysfunction. The underlying disease genes encode factors involved in various aspects of mitochondrial protein homeostasis, including proteases and chaperones, mitochondrial protein import machinery, mediators of inner mitochondrial membrane lipid homeostasis, and aminoacylation of mitochondrial tRNAs required for translation. We further discuss a complex of frequently associated phenotypes (short stature, cataracts, and cardiomyopathy) potentially explained by alterations to steroidogenesis, a process regulated by mitochondria. Together, these observations provide novel insight into the consequences of impaired mitochondrial protein homeostasis.

scholarly journals Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies

2020 ◽  
Vol 295 (30) ◽  
pp. 10138-10152 ◽  
Author(s):  
Janin Lautenschläger ◽  
Sara Wagner-Valladolid ◽  
Amberley D. Stephens ◽  
Ana Fernández-Villegas ◽  
Colin Hockings ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Protein Import ◽  
Protein Quality ◽  
Neurodegenerative Disorder ◽  
Mitochondrial Protein ◽  
Amyloid Β ◽  
Ubiquitin Proteasome System ◽  
Protein Homeostasis ◽  
Mitochondrial Inhibitors ◽  
Ubiquitin Proteasome

Mitochondrial dysfunction has long been implicated in the neurodegenerative disorder Parkinson's disease (PD); however, it is unclear how mitochondrial impairment and α-synuclein pathology are coupled. Using specific mitochondrial inhibitors, EM analysis, and biochemical assays, we report here that intramitochondrial protein homeostasis plays a major role in α-synuclein aggregation. We found that interference with intramitochondrial proteases, such as HtrA2 and Lon protease, and mitochondrial protein import significantly aggravates α-synuclein seeding. In contrast, direct inhibition of mitochondrial complex I, an increase in intracellular calcium concentration, or formation of reactive oxygen species, all of which have been associated with mitochondrial stress, did not affect α-synuclein pathology. We further demonstrate that similar mechanisms are involved in amyloid-β 1-42 (Aβ42) aggregation. Our results suggest that, in addition to other protein quality control pathways, such as the ubiquitin–proteasome system, mitochondria per se can influence protein homeostasis of cytosolic aggregation-prone proteins. We propose that approaches that seek to maintain mitochondrial fitness, rather than target downstream mitochondrial dysfunction, may aid in the search for therapeutic strategies to manage PD and related neuropathologies.

scholarly journals Reversal of mitochondrial proteomic loss in Type 1 diabetic heart with overexpression of phospholipid hydroperoxide glutathione peroxidase

2013 ◽  
Vol 304 (7) ◽  
pp. R553-R565 ◽  
Author(s):  
Walter A. Baseler ◽  
Erinne R. Dabkowski ◽  
Rajaganapathi Jagannathan ◽  
Dharendra Thapa ◽  
Cody E. Nichols ◽  
...  
Keyword(s):  
Glutathione Peroxidase ◽  
Mitochondrial Dysfunction ◽  
Protein Import ◽  
Contractile Function ◽  
Tricarboxylic Acid Cycle ◽  
Mitochondrial Protein ◽  
Diabetic Heart ◽  
Phospholipid Hydroperoxide Glutathione Peroxidase ◽  
Mitochondrial Protein Import ◽  
Phospholipid Hydroperoxide

Mitochondrial dysfunction is a contributor to diabetic cardiomyopathy. Previously, we observed proteomic decrements within the inner mitochondrial membrane (IMM) and matrix of diabetic cardiac interfibrillar mitochondria (IFM) correlating with dysfunctional mitochondrial protein import. The goal of this study was to determine whether overexpression of mitochondria phospholipid hydroperoxide glutathione peroxidase 4 (mPHGPx), an antioxidant enzyme capable of scavenging membrane-associated lipid peroxides in the IMM, could reverse proteomic alterations, dysfunctional protein import, and ultimately, mitochondrial dysfunction associated with the diabetic heart. MPHGPx transgenic mice and controls were made diabetic by multiple low-dose streptozotocin injections and examined after 5 wk of hyperglycemia. Five weeks after hyperglycemia onset, in vivo analysis of cardiac contractile function revealed decreased ejection fraction and fractional shortening in diabetic hearts that was reversed with mPHGPx overexpression. MPHGPx overexpression increased electron transport chain function while attenuating hydrogen peroxide production and lipid peroxidation in diabetic mPHGPx IFM. MPHGPx overexpression lessened proteomic loss observed in diabetic IFM. Posttranslational modifications, including oxidations and deamidations, were attenuated in diabetic IFM with mPHGPx overexpression. Mitochondrial protein import dysfunction in diabetic IFM was reversed with mPHGPx overexpression correlating with protein import constituent preservation. Ingenuity Pathway Analyses indicated that oxidative phosphorylation, tricarboxylic acid cycle, and fatty acid oxidation processes most influenced in diabetic IFM were preserved by mPHGPx overexpression. Specific mitochondrial networks preserved included complex I and II, mitochondrial ultrastructure, and mitochondrial protein import. These results indicate that mPHGPx overexpression can preserve the mitochondrial proteome and provide cardioprotective benefits to the diabetic heart.

scholarly journals Events upstream of mitochondrial protein import limit the oxidative capacity of fibroblasts in multiple mitochondrial disease

2002 ◽  
Vol 1586 (2) ◽  
pp. 146-154 ◽  
Author(s):  
Arne A. Rungi ◽  
Andy Primeau ◽  
Lorraine Nunes Christie ◽  
Joseph W. Gordon ◽  
Brian H. Robinson ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Oxidative Capacity ◽  
Mitochondrial Protein Import

scholarly journals The Dimensions of Primary Mitochondrial Disorders

2020 ◽  
Vol 8 ◽  
Author(s):  
Lea D. Schlieben ◽  
Holger Prokisch
Keyword(s):  
Energy Metabolism ◽  
Mitochondrial Disease ◽  
Nuclear Dna ◽  
Protein Localization ◽  
Mitochondrial Protein ◽  
Mitochondrial Disorder ◽  
Mitochondrial Disorders ◽  
Disease Genes ◽  
Mitochondrial Energy Metabolism ◽  
Vast Number

The concept of a mitochondrial disorder was initially described in 1962, in a patient with altered energy metabolism. Over time, mitochondrial energy metabolism has been discovered to be influenced by a vast number of proteins with a multitude of functional roles. Amongst these, defective oxidative phosphorylation arose as the hallmark of mitochondrial disorders. In the premolecular era, the diagnosis of mitochondrial disease was dependent on biochemical criteria, with inherent limitations such as tissue availability and specificity, preanalytical and analytical artifacts, and secondary effects. With the identification of the first mitochondrial disease-causing mutations, the genetic complexity of mitochondrial disorders began to unravel. Mitochondrial dysfunctions can be caused by pathogenic variants in genes encoded by the mitochondrial DNA or the nuclear DNA, and can display heterogenous phenotypic manifestations. The application of next generation sequencing methodologies in diagnostics is proving to be pivotal in finding the molecular diagnosis and has been instrumental in the discovery of a growing list of novel mitochondrial disease genes. In the molecular era, the diagnosis of a mitochondrial disorder, suspected on clinical grounds, is increasingly based on variant detection and associated statistical support, while invasive biopsies and biochemical assays are conducted to an ever-decreasing extent. At present, there is no uniform biochemical or molecular definition for the designation of a disease as a “mitochondrial disorder”. Such designation is currently dependent on the criteria applied, which may encompass clinical, genetic, biochemical, functional, and/or mitochondrial protein localization criteria. Given this variation, numerous gene lists emerge, ranging from 270 to over 400 proposed mitochondrial disease genes. Herein we provide an overview of the mitochondrial disease associated genes and their accompanying challenges.

scholarly journals Mitochondrial Dysfunction: Different Routes to Alzheimer’s Disease Therapy

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Pasquale Picone ◽  
Domenico Nuzzo ◽  
Luca Caruana ◽  
Valeria Scafidi ◽  
Marta Di Carlo
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Permeability Transition ◽  
Mitochondrial Protein ◽  
Radical Scavenging ◽  
Permeability Transition ◽  
Oxidation Potential ◽  
Mitochondrial Functions

Mitochondria are dynamic ATP-generating organelle which contribute to many cellular functions including bioenergetics processes, intracellular calcium regulation, alteration of reduction-oxidation potential of cells, free radical scavenging, and activation of caspase mediated cell death. Mitochondrial functions can be negatively affected by amyloidβpeptide (Aβ), an important component in Alzheimer’s disease (AD) pathogenesis, and Aβcan interact with mitochondria and cause mitochondrial dysfunction. One of the most accepted hypotheses for AD onset implicates that mitochondrial dysfunction and oxidative stress are one of the primary events in the insurgence of the pathology. Here, we examine structural and functional mitochondrial changes in presence of Aβ. In particular we review data concerning Aβimport into mitochondrion and its involvement in mitochondrial oxidative stress, bioenergetics, biogenesis, trafficking, mitochondrial permeability transition pore (mPTP) formation, and mitochondrial protein interaction. Moreover, the development of AD therapy targeting mitochondria is also discussed.

scholarly journals Residues of Tim44 Involved in both Association with the Translocon of the Inner Mitochondrial Membrane and Regulation of Mitochondrial Hsp70 Tethering

2008 ◽  
Vol 28 (13) ◽  
pp. 4424-4433 ◽  
Author(s):  
Dirk Schiller ◽  
Yu Chin Cheng ◽  
Qinglian Liu ◽  
William Walter ◽  
Elizabeth A. Craig
Keyword(s):  
Amino Acid ◽  
Protein Import ◽  
Protein Translocation ◽  
Mitochondrial Protein ◽  
Inner Mitochondrial Membrane ◽  
The Matrix ◽  
Mitochondrial Hsp70 ◽  
Amino Acid Segment

ABSTRACT Translocation of proteins from the cytosol across the mitochondrial inner membrane is driven by the action of the import motor, which is associated with the translocon on the matrix side of the membrane. It is well established that an essential peripheral membrane protein, Tim44, tethers mitochondrial Hsp70 (mtHsp70), the core of the import motor, to the translocon. This Tim44-mtHsp70 interaction, which can be recapitulated in vitro, is destabilized by binding of mtHsp70 to a substrate polypeptide. Here we report that the N-terminal 167-amino-acid segment of mature Tim44 is sufficient for both interaction with mtHsp70 and destabilization of a Tim44-mtHsp70 complex caused by client protein binding. Amino acid alterations within a 30-amino-acid segment affected both the release of mtHsp70 upon peptide binding and the interaction of Tim44 with the translocon. Our results support the idea that Tim44 plays multiple roles in mitochondrial protein import by recruiting Ssc1 and its J protein cochaperone to the translocon and coordinating their interactions to promote efficient protein translocation in vivo.

scholarly journals Coordination and assembly of protein complexes encoded across mitochondrial and nuclear genomes is assisted by CLPP2 in Arabidopsis thaliana

2020 ◽  
Author(s):  
Jakob Petereit ◽  
Owen Duncan ◽  
Monika W Murcha ◽  
Ricarda Fenske ◽  
Emilia Cincu ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Protein Degradation ◽  
Protein Import ◽  
Protein Complexes ◽  
Single Gene ◽  
Mitochondrial Protein ◽  
Protein Homeostasis ◽  
Knock Out ◽  
Genes Encoding ◽  
Nuclear Genomes

AbstractProtein homeostasis in eukaryotic organelles and their progenitor prokaryotes is regulated by a series of proteases including the caseinolytic protease (CLPP). CLPP has essential roles in chloroplast biogenesis and maintenance, but the significance of the plant mitochondrial CLPP remains unknown and factors that aid coordination of nuclear and mitochondrial encoded subunits for complex assembly in mitochondria await discovery. We generated knock-out lines of the single gene for the mitochondrial CLP protease subunit, CLPP2, in Arabidopsis thaliana. Mutants had higher abundance of transcripts from mitochondrial genes encoding OXPHOS protein complexes, while transcripts for nuclear genes encoding other subunits of the same complexes showed no change in abundance. In contrast, the protein abundance of specific nuclear-encoded subunits in OXPHOS complexes I and V increased in CLPP2 knockouts, without accumulation of mitochondrial-encoded counterparts in the same complex. Protein complexes mainly or entirely encoded in the nucleus were unaffected. Analysis of protein import, assembly and function of Complex I revealed that while function was retained, protein homeostasis was disrupted through decreased assembly, leading to accumulation of soluble subcomplexes of nuclear-encoded subunits. Therefore, CLPP2 contributes to the mitochondrial protein degradation network through supporting coordination and assembly of protein complexes encoded across mitochondrial and nuclear genomes.One sentence summaryCLPP contributes to the mitochondrial protein degradation network through supporting coordination and assembly of protein complexes encoded across mitochondrial and nuclear genomes.

Mitochondrial diseases caused by dysfunctional mitochondrial protein import

2018 ◽  
Vol 46 (5) ◽  
pp. 1225-1238 ◽  
Author(s):  
Thomas Daniel Jackson ◽  
Catherine Sarah Palmer ◽  
Diana Stojanovski
Keyword(s):  
Mitochondrial Disease ◽  
Genetic Disease ◽  
Molecular Basis ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Mitochondrial Diseases ◽  
Mitochondrial Proteins ◽  
Eukaryotic Cells ◽  
Mitochondrial Protein Import ◽  
Mitochondrial Proteome

Mitochondria are essential organelles which perform complex and varied functions within eukaryotic cells. Maintenance of mitochondrial health and functionality is thus a key cellular priority and relies on the organelle's extensive proteome. The mitochondrial proteome is largely encoded by nuclear genes, and mitochondrial proteins must be sorted to the correct mitochondrial sub-compartment post-translationally. This essential process is carried out by multimeric and dynamic translocation and sorting machineries, which can be found in all four mitochondrial compartments. Interestingly, advances in the diagnosis of genetic disease have revealed that mutations in various components of the human import machinery can cause mitochondrial disease, a heterogenous and often severe collection of disorders associated with energy generation defects and a multisystem presentation often affecting the cardiovascular and nervous systems. Here, we review our current understanding of mitochondrial protein import systems in human cells and the molecular basis of mitochondrial diseases caused by defects in these pathways.

scholarly journals Small mitochondrial protein NERCLIN regulates cardiolipin homeostasis and mitochondrial ultrastructure

2021 ◽  
Author(s):  
Svetlana Konovalova ◽  
Rubén Torregrosa-Muñumer ◽  
Pooja Manjunath ◽  
Sundar Baral ◽  
Xiaonan Liu ◽  
...  
Keyword(s):  
Lipid Analysis ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Protein ◽  
Membrane Lipid ◽  
Negative Regulator ◽  
Mitochondrial Ultrastructure ◽  
Inner Mitochondrial Membrane ◽  
The Matrix ◽  
And Function ◽  
Regulatory Functions

ABSTRACTCardiolipin (CL) is an essential phospholipid for mitochondrial structure and function. Here we present a small mitochondrial protein, NERCLIN, as a negative regulator of CL homeostasis and mitochondrial ultrastructure. Primate-specific NERCLIN is expressed ubiquitously from GRPEL2 locus on a tightly regulated low level, but induced by heat stress. NERCLIN overexpression severely disrupts mitochondrial cristae structure and induces mitochondrial fragmentation. Proximity labeling suggested interactions of NERCLIN with CL synthesis and prohibitin complexes on the matrix side of the inner mitochondrial membrane. Lipid analysis indicated that NERCLIN regulates mitochondrial CL content. The regulation may occur directly through interaction with PTPMT1, a proximal partner on the CL synthesis pathway, as its product phosphatidylglycerol was also reduced by NERCLIN. We propose that NERCLIN contributes to stress-induced adaptation of mitochondrial dynamics and turnover by regulating the mitochondrial CL content. Our findings add NERCLIN to the group of recently identified small mitochondrial proteins with important regulatory functions.

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