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Open AccessArticle

Biological Implications of Differential Expression of Mitochondrial-Shaping Proteins in Parkinson’s Disease

by Sara Rocha, Ana Freitas, Sofia C. Guimaraes, Rui Vitorino, Miguel Aroso and Maria Gomez-Lazaro

Antioxidants 2018, 7(1), 1; https://doi.org/10.3390/antiox7010001 - 21 Dec 2017

Cited by 15 | Viewed by 6990

Abstract

It has long been accepted that mitochondrial function and morphology is affected in Parkinson’s disease, and that mitochondrial function can be directly related to its morphology. So far, mitochondrial morphological alterations studies, in the context of this neurodegenerative disease, have been performed through [...] Read more.

It has long been accepted that mitochondrial function and morphology is affected in Parkinson’s disease, and that mitochondrial function can be directly related to its morphology. So far, mitochondrial morphological alterations studies, in the context of this neurodegenerative disease, have been performed through microscopic methodologies. The goal of the present work is to address if the modifications in the mitochondrial-shaping proteins occurring in this disorder have implications in other cellular pathways, which might constitute important pathways for the disease progression. To do so, we conducted a novel approach through a thorough exploration of the available proteomics-based studies in the context of Parkinson’s disease. The analysis provided insight into the altered biological pathways affected by changes in the expression of mitochondrial-shaping proteins via different bioinformatic tools. Unexpectedly, we observed that the mitochondrial-shaping proteins altered in the context of Parkinson’s disease are, in the vast majority, related to the organization of the mitochondrial cristae. Conversely, in the studies that have resorted to microscopy-based techniques, the most widely reported alteration in the context of this disorder is mitochondria fragmentation. Cristae membrane organization is pivotal for mitochondrial ATP production, and changes in their morphology have a direct impact on the organization and function of the oxidative phosphorylation (OXPHOS) complexes. To understand which biological processes are affected by the alteration of these proteins we analyzed the binding partners of the mitochondrial-shaping proteins that were found altered in Parkinson’s disease. We showed that the binding partners fall into seven different cellular components, which include mitochondria, proteasome, and endoplasmic reticulum (ER), amongst others. It is noteworthy that, by evaluating the biological process in which these modified proteins are involved, we showed that they are related to the production and metabolism of ATP, immune response, cytoskeleton alteration, and oxidative stress, amongst others. In summary, with our bioinformatics approach using the data on the modified proteins in Parkinson’s disease patients, we were able to relate the alteration of mitochondrial-shaping proteins to modifications of crucial cellular pathways affected in this disease. Full article

(This article belongs to the Special Issue Mitochondrial Shape Change in Physio-Pathology)

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Review

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27 pages, 1011 KiB

Open AccessReview

Adrenergic Regulation of Drp1-Driven Mitochondrial Fission in Cardiac Physio-Pathology

by Bong Sook Jhun, Jin O-Uchi, Stephanie M. Adaniya, Michael W. Cypress and Yisang Yoon

Antioxidants 2018, 7(12), 195; https://doi.org/10.3390/antiox7120195 - 18 Dec 2018

Cited by 32 | Viewed by 10409

Abstract

Abnormal mitochondrial morphology, especially fragmented mitochondria, and mitochondrial dysfunction are hallmarks of a variety of human diseases including heart failure (HF). Although emerging evidence suggests a link between mitochondrial fragmentation and cardiac dysfunction, it is still not well described which cardiac signaling pathway [...] Read more.

Abnormal mitochondrial morphology, especially fragmented mitochondria, and mitochondrial dysfunction are hallmarks of a variety of human diseases including heart failure (HF). Although emerging evidence suggests a link between mitochondrial fragmentation and cardiac dysfunction, it is still not well described which cardiac signaling pathway regulates mitochondrial morphology and function under pathophysiological conditions such as HF. Mitochondria change their shape and location via the activity of mitochondrial fission and fusion proteins. This mechanism is suggested as an important modulator for mitochondrial and cellular functions including bioenergetics, reactive oxygen species (ROS) generation, spatiotemporal dynamics of Ca²⁺ signaling, cell growth, and death in the mammalian cell- and tissue-specific manners. Recent reports show that a mitochondrial fission protein, dynamin-like/related protein 1 (DLP1/Drp1), is post-translationally modified via cell signaling pathways, which control its subcellular localization, stability, and activity in cardiomyocytes/heart. In this review, we summarize the possible molecular mechanisms for causing post-translational modifications (PTMs) of DLP1/Drp1 in cardiomyocytes, and further discuss how these PTMs of DLP1/Drp1 mediate abnormal mitochondrial morphology and mitochondrial dysfunction under adrenergic signaling activation that contributes to the development and progression of HF. Full article

(This article belongs to the Special Issue Mitochondrial Shape Change in Physio-Pathology)

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21 pages, 1510 KiB

Open AccessReview

Mitochondrial Membrane Dynamics—Functional Positioning of OPA1

by Hakjoo Lee and Yisang Yoon

Antioxidants 2018, 7(12), 186; https://doi.org/10.3390/antiox7120186 - 08 Dec 2018

Cited by 41 | Viewed by 9018

Abstract

The maintenance of mitochondrial energetics requires the proper regulation of mitochondrial morphology, and vice versa. Mitochondrial dynamins control mitochondrial morphology by mediating fission and fusion. One of them, optic atrophy 1 (OPA1), is the mitochondrial inner membrane remodeling protein. OPA1 has a dual [...] Read more.

The maintenance of mitochondrial energetics requires the proper regulation of mitochondrial morphology, and vice versa. Mitochondrial dynamins control mitochondrial morphology by mediating fission and fusion. One of them, optic atrophy 1 (OPA1), is the mitochondrial inner membrane remodeling protein. OPA1 has a dual role in maintaining mitochondrial morphology and energetics through mediating inner membrane fusion and maintaining the cristae structure. OPA1 is expressed in multiple variant forms through alternative splicing and post-translational proteolytic cleavage, but the functional differences between these variants have not been completely understood. Recent studies generated new information regarding the role of OPA1 cleavage. In this review, we will first provide a brief overview of mitochondrial membrane dynamics by describing fission and fusion that are mediated by mitochondrial dynamins. The second part describes OPA1-mediated fusion and energetic maintenance, the role of OPA1 cleavage, and a new development in OPA1 function, in which we will provide new insight for what OPA1 does and what proteolytic cleavage of OPA1 is for. Full article

(This article belongs to the Special Issue Mitochondrial Shape Change in Physio-Pathology)

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12 pages, 862 KiB

Open AccessReview

Morphological Pathways of Mitochondrial Division

by Bernard Tandler, Charles L. Hoppel and Jason A. Mears

Antioxidants 2018, 7(2), 30; https://doi.org/10.3390/antiox7020030 - 15 Feb 2018

Cited by 18 | Viewed by 5538

Abstract

Mitochondrial fission is essential for distributing cellular energy throughout cells and for isolating damaged regions of the organelle that are targeted for degradation. Excessive fission is associated with the progression of cell death as well. Therefore, this multistep process is tightly regulated and [...] Read more.

Mitochondrial fission is essential for distributing cellular energy throughout cells and for isolating damaged regions of the organelle that are targeted for degradation. Excessive fission is associated with the progression of cell death as well. Therefore, this multistep process is tightly regulated and several physiologic cues directly impact mitochondrial division. The double membrane structure of mitochondria complicates this process, and protein factors that drive membrane scission need to coordinate the separation of both the outer and inner mitochondrial membranes. In this review, we discuss studies that characterize distinct morphological changes associated with mitochondrial division. Specifically, coordinated partitioning and pinching of mitochondria have been identified as alternative mechanisms associated with fission. Additionally, we highlight the major protein constituents that drive mitochondrial fission and the role of connections with the endoplasmic reticulum in establishing sites of membrane division. Collectively, we review decades of research that worked to define the molecular framework of mitochondrial fission. Ongoing studies will continue to sort through the complex network of interactions that drive this critical event. Full article

(This article belongs to the Special Issue Mitochondrial Shape Change in Physio-Pathology)

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18 pages, 816 KiB

Open AccessReview

Metabolic Alterations in Cancer Cells and the Emerging Role of Oncometabolites as Drivers of Neoplastic Change

by Zhengqiu Zhou, Elochukwu Ibekwe and Yevgen Chornenkyy

Antioxidants 2018, 7(1), 16; https://doi.org/10.3390/antiox7010016 - 17 Jan 2018

Cited by 30 | Viewed by 9295

Abstract

The mitochondrion is an important organelle and provides energy for a plethora of intracellular reactions. Metabolic dysregulation has dire consequences for the cell, and alteration in metabolism has been identified in multiple disease states—cancer being one. Otto Warburg demonstrated that cancer cells, in [...] Read more.

The mitochondrion is an important organelle and provides energy for a plethora of intracellular reactions. Metabolic dysregulation has dire consequences for the cell, and alteration in metabolism has been identified in multiple disease states—cancer being one. Otto Warburg demonstrated that cancer cells, in the presence of oxygen, undergo glycolysis by reprogramming their metabolism—termed “aerobic glycolysis”. Alterations in metabolism enable cancer cells to gain a growth advantage by obtaining precursors for macromolecule biosynthesis, such as nucleic acids and lipids. To date, several molecules, termed “oncometabolites”, have been identified to be elevated in cancer cells and arise from mutations in nuclear encoded mitochondrial enzymes. Furthermore, there is evidence that oncometabolites can affect mitochondrial dynamics. It is believed that oncometabolites can assist in reprogramming enzymatic pathways and providing cancer cells with selective advantages. In this review, we will touch upon the effects of normal and aberrant mitochondrial metabolism in normal and cancer cells, the advantages of metabolic reprogramming, effects of oncometabolites on metabolism and mitochondrial dynamics and therapies aimed at targeting oncometabolites and metabolic aberrations. Full article

(This article belongs to the Special Issue Mitochondrial Shape Change in Physio-Pathology)

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15 pages, 994 KiB

Open AccessReview

Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

by Sumaira Ali and Gavin P. McStay

Antioxidants 2018, 7(1), 15; https://doi.org/10.3390/antiox7010015 - 17 Jan 2018

Cited by 19 | Viewed by 5787

Abstract

The mitochondrial network is a dynamic organization within eukaryotic cells that participates in a variety of essential cellular processes, such as adenosine triphosphate (ATP) synthesis, central metabolism, apoptosis and inflammation. The mitochondrial network is balanced between rates of fusion and fission that respond [...] Read more.

The mitochondrial network is a dynamic organization within eukaryotic cells that participates in a variety of essential cellular processes, such as adenosine triphosphate (ATP) synthesis, central metabolism, apoptosis and inflammation. The mitochondrial network is balanced between rates of fusion and fission that respond to pathophysiologic signals to coordinate appropriate mitochondrial processes. Mitochondrial fusion and fission are regulated by proteins that either reside in or translocate to the inner or outer mitochondrial membranes or are soluble in the inter-membrane space. Mitochondrial fission and fusion are performed by guanosine triphosphatases (GTPases) on the outer and inner mitochondrial membranes with the assistance of other mitochondrial proteins. Due to the essential nature of mitochondrial function for cellular homeostasis, regulation of mitochondrial dynamics is under strict control. Some of the mechanisms used to regulate the function of these proteins are post-translational proteolysis and/or turnover, and this review will discuss these mechanisms required for correct mitochondrial network organization. Full article

(This article belongs to the Special Issue Mitochondrial Shape Change in Physio-Pathology)

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24 pages, 1168 KiB

Open AccessReview

Reactive Oxygen Species and Mitochondrial Dynamics: The Yin and Yang of Mitochondrial Dysfunction and Cancer Progression

by Jan Ježek, Katrina F. Cooper and Randy Strich

Antioxidants 2018, 7(1), 13; https://doi.org/10.3390/antiox7010013 - 16 Jan 2018

Cited by 331 | Viewed by 16987

Abstract

Mitochondria are organelles with a highly dynamic ultrastructure maintained by a delicate equilibrium between its fission and fusion rates. Understanding the factors influencing this balance is important as perturbations to mitochondrial dynamics can result in pathological states. As a terminal site of nutrient [...] Read more.

Mitochondria are organelles with a highly dynamic ultrastructure maintained by a delicate equilibrium between its fission and fusion rates. Understanding the factors influencing this balance is important as perturbations to mitochondrial dynamics can result in pathological states. As a terminal site of nutrient oxidation for the cell, mitochondrial powerhouses harness energy in the form of ATP in a process driven by the electron transport chain. Contemporaneously, electrons translocated within the electron transport chain undergo spontaneous side reactions with oxygen, giving rise to superoxide and a variety of other downstream reactive oxygen species (ROS). Mitochondrially-derived ROS can mediate redox signaling or, in excess, cause cell injury and even cell death. Recent evidence suggests that mitochondrial ultrastructure is tightly coupled to ROS generation depending on the physiological status of the cell. Yet, the mechanism by which changes in mitochondrial shape modulate mitochondrial function and redox homeostasis is less clear. Aberrant mitochondrial morphology may lead to enhanced ROS formation, which, in turn, may deteriorate mitochondrial health and further exacerbate oxidative stress in a self-perpetuating vicious cycle. Here, we review the latest findings on the intricate relationship between mitochondrial dynamics and ROS production, focusing mainly on its role in malignant disease. Full article

(This article belongs to the Special Issue Mitochondrial Shape Change in Physio-Pathology)

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21 pages, 1542 KiB

Open AccessReview

Exercise and Mitochondrial Dynamics: Keeping in Shape with ROS and AMPK

by Adam J. Trewin, Brandon J. Berry and Andrew P. Wojtovich

Antioxidants 2018, 7(1), 7; https://doi.org/10.3390/antiox7010007 - 06 Jan 2018

Cited by 91 | Viewed by 14220

Abstract

Exercise is a robust stimulus for mitochondrial adaptations in skeletal muscle which consequently plays a central role in enhancing metabolic health. Despite this, the precise molecular events that underpin these beneficial effects remain elusive. In this review, we discuss molecular signals generated during [...] Read more.

Exercise is a robust stimulus for mitochondrial adaptations in skeletal muscle which consequently plays a central role in enhancing metabolic health. Despite this, the precise molecular events that underpin these beneficial effects remain elusive. In this review, we discuss molecular signals generated during exercise leading to altered mitochondrial morphology and dynamics. In particular, we focus on the interdependence between reactive oxygen species (ROS) and redox homeostasis, the sensing of cellular bioenergetic status via 5’ adenosine monophosphate (AMP)-activated protein kinase (AMPK), and the regulation of mitochondrial fission and fusion. Precisely how exercise regulates the network of these responses and their effects on mitochondrial dynamics is not fully understood at present. We highlight the limitations that exist with the techniques currently available, and discuss novel molecular tools to potentially advance the fields of redox biology and mitochondrial bioenergetics. Ultimately, a greater understanding of these processes may lead to novel mitochondria-targeted therapeutic strategies to augment or mimic exercise in order to attenuate or reverse pathophysiology. Full article

(This article belongs to the Special Issue Mitochondrial Shape Change in Physio-Pathology)

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924 KiB

Open AccessReview

The Interplay between Oncogenic Signaling Networks and Mitochondrial Dynamics

by Sarbajeet Nagdas and David F. Kashatus

Antioxidants 2017, 6(2), 33; https://doi.org/10.3390/antiox6020033 - 17 May 2017

Cited by 33 | Viewed by 7352

Abstract

Mitochondria are dynamic organelles that alter their organization in response to a variety of cellular cues. Mitochondria are central in many biologic processes, such as cellular bioenergetics and apoptosis, and mitochondrial network morphology can contribute to those physiologic processes. Some of the biologic [...] Read more.

Mitochondria are dynamic organelles that alter their organization in response to a variety of cellular cues. Mitochondria are central in many biologic processes, such as cellular bioenergetics and apoptosis, and mitochondrial network morphology can contribute to those physiologic processes. Some of the biologic processes that are in part governed by mitochondria are also commonly deregulated in cancers. Furthermore, patient tumor samples from a variety of cancers have revealed that mitochondrial dynamics machinery may be deregulated in tumors. In this review, we will discuss how commonly mutated oncogenes and their downstream effector pathways regulate the mitochondrial dynamics machinery to promote changes in mitochondrial morphology as well as the physiologic consequences of altered mitochondrial morphology for tumorigenic growth. Full article

(This article belongs to the Special Issue Mitochondrial Shape Change in Physio-Pathology)

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811 KiB

Open AccessReview

Abnormalities of Mitochondrial Dynamics in Neurodegenerative Diseases

by Ju Gao, Luwen Wang, Jingyi Liu, Fei Xie, Bo Su and Xinglong Wang

Antioxidants 2017, 6(2), 25; https://doi.org/10.3390/antiox6020025 - 05 Apr 2017

Cited by 177 | Viewed by 15212

Abstract

Neurodegenerative diseases are incurable and devastating neurological disorders characterized by the progressive loss of the structure and function of neurons in the central nervous system or peripheral nervous system. Mitochondria, organelles found in most eukaryotic cells, are essential for neuronal survival and are [...] Read more.

Neurodegenerative diseases are incurable and devastating neurological disorders characterized by the progressive loss of the structure and function of neurons in the central nervous system or peripheral nervous system. Mitochondria, organelles found in most eukaryotic cells, are essential for neuronal survival and are involved in a number of neuronal functions. Mitochondrial dysfunction has long been demonstrated as a common prominent early pathological feature of a variety of common neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). Mitochondria are highly dynamic organelles that undergo continuous fusion, fission, and transport, the processes of which not only control mitochondrial morphology and number but also regulate mitochondrial function and location. The importance of mitochondrial dynamics in the pathogenesis of neurodegenerative diseases has been increasingly unraveled after the identiﬁcation of several key fusion and fission regulators such as Drp1, OPA1, and mitofusins. In this review, after a brief discussion of molecular mechanisms regulating mitochondrial fusion, fission, distribution, and trafficking, as well as the important role of mitochondrial dynamics for neuronal function, we review previous and the most recent studies about mitochondrial dynamic abnormalities observed in various major neurodegenerative diseases and discuss the possibility of targeting mitochondrial dynamics as a likely novel therapeutic strategy for neurodegenerative diseases. Full article

(This article belongs to the Special Issue Mitochondrial Shape Change in Physio-Pathology)

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