bims-drumid 2024-11-10 papers

bims-drumid

Biomed News

on Drugs for mitochondrial diseases

Issue of 2024‒11‒10
nine papers selected by
Volkmar Weissig, Midwestern University

Small Molecules Targeting Mitochondria: A Mechanistic Approach to Combating Doxorubicin-Induced Cardiotoxicity.
The Emerging Role of Brain Mitochondria in Fear and Anxiety.
Convergence between brain aging and Alzheimer's disease: focus on mitochondria.
Mitochondria in skeletal system-related diseases.
Analysis of mitochondrial biogenesis regulation by oxidative stress.
Mitochondrial oxidative stress in immunopathogenesis of diseases.
The multifaceted modulation of mitochondrial metabolism in tumorigenesis.
Scientific investigation of non-coding RNAs in mitochondrial epigenetic and aging disorders: Current nanoengineered approaches for their therapeutic improvement.
Does a transmembrane sodium gradient control membrane potential in mammalian mitochondria?

Cardiovasc Toxicol. 2024 Nov 04.

Small Molecules Targeting Mitochondria: A Mechanistic Approach to Combating Doxorubicin-Induced Cardiotoxicity.

Chinmay Pal.

  Doxorubicin (Dox) is a commonly used chemotherapy drug effective against a range of cancers, but its clinical application is greatly limited by dose-dependent and cumulative cardiotoxicity. Mitochondrial dysfunction is recognized as a key factor in Dox-induced cardiotoxicity, leading to oxidative stress, disrupted calcium balance, and activation of apoptotic pathways. Recent research has emphasized the potential of small molecules that specifically target mitochondria to alleviate these harmful effects. This review provides a comprehensive analysis of small molecules that offer cardioprotection by preserving mitochondrial function in the context of doxorubicin-induced cardiotoxicity (DIC). The mechanisms of action include the reduction of reactive oxygen species (ROS) production, stabilization of mitochondrial membrane potential, enhancement of mitochondrial biogenesis, and modulation of key signaling pathways involved in cell survival and apoptosis. By targeting mitochondria, these small molecules present a promising therapeutic strategy to prevent or reduce the cardiotoxic effects associated with Dox treatment. This review not only discusses the mechanistic actions of these agents but also emphasizes their potential in improving cardiovascular outcomes for cancer patients. Gaining insight into these mechanisms can help in creating more effective strategies to safeguard the heart during chemotherapy, allowing for the ongoing use of Dox with a lower risk to the patient's cardiovascular health. This review highlights the critical role of mitochondria-targeted therapies as a promising approach in addressing DIC.

Keywords:  Apoptosis; Cardiotoxicity; Doxorubicin; Mitochondria; Reactive oxygen species; Small molecules

DOI:  https://doi.org/10.1007/s12012-024-09941-7
Curr Top Behav Neurosci. 2024 Nov 07.

The Emerging Role of Brain Mitochondria in Fear and Anxiety.

Alessandro Chioino, Carmen Sandi.

  The functional complexity of brain circuits underlies the broad spectrum of behaviors, cognitive functions, and their associated disorders. Mitochondria, traditionally known for their role in cellular energy metabolism, are increasingly recognized as central to brain function and behavior. This review examines how mitochondria are pivotal in linking cellular energy processes with the functioning of neural circuits that govern fear and anxiety. Following an introductory section in which we summarize current knowledge about fear and anxiety neural circuits, we provide a brief summary of mitochondria fundamental roles (e.g., from energy production and calcium buffering to their involvement in reactive oxygen species (ROS) generation, mitochondrial dynamics, and signaling), particularly emphasizing their contribution to synaptic plasticity, neurodevelopment, and stress response mechanisms. The review's core focuses on the current state of knowledge regarding how mitochondrial function and dysfunction impact the neural substrates of fear and anxiety. Furthermore, we explore the implications of mitochondrial alterations in the context of posttraumatic stress disorder (PTSD) and anxiety disorders, underscoring the potential of mitochondrial pathways as new therapeutic targets. Integrating insights from genetic, biochemical, neurobiological, behavioral, and clinical studies, we propose a model in which mitochondrial function is critical for regulating the neural circuits that underpin fear and anxiety behaviors, highlighting how mitochondrial dysfunction can lead to their pathological manifestations. This integration emphasizes the potential for developing novel treatments targeting the biological roots of fear, anxiety, and related disorders. By merging mitochondrial biology with behavioral and circuit neuroscience, we enrich our neurobiological understanding of fear and anxiety, uncovering promising avenues for therapeutic intervention.

Keywords:  Anxiety; Fear; Mitochondria; Neural circuits; Nutritional interventions

DOI:  https://doi.org/10.1007/7854_2024_537
Mech Ageing Dev. 2024 Oct 25. pii: S0047-6374(24)00101-5. [Epub ahead of print] 112001

Convergence between brain aging and Alzheimer's disease: focus on mitochondria.

Salvatore Vaiasicca, Marta Balietti, Lisa Bevilacqua, Belinda Giorgetti, Tiziana Casoli.

  Alzheimer's disease (AD) accounts for the majority of dementia cases, with aging being the primary risk factor for developing this neurodegenerative condition. Aging and AD share several characteristics, including the formation of amyloid plaques and neurofibrillary tangles, synaptic loss, and neuroinflammation. This overlap suggests that mechanisms driving the aging process might also promote AD; however, the underlying processes are not yet fully understood. In this narrative review, we will focus on the role of mitochondria, not only as the "powerhouse of the cell", but also in programmed cell death, immune response, macromolecular synthesis, and calcium regulation. We will explore both the common changes between aging and AD and the differences between them. Additionally, we will provide an overview of interventions aimed at maintaining mitochondrial function in an attempt to slow the progression of AD. This will include a discussion of antioxidant molecules, factors that trigger mitochondrial biogenesis, compounds capable of restoring the fission/fusion balance, and a particular focus on recent techniques for mitochondrial DNA gene therapy.

Keywords:  Alzheimer’s disease; aging; calcium homeostasis; mitochondrial DNA; mitochondrial membrane dynamics; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.mad.2024.112001
Biomed Pharmacother. 2024 Nov 04. pii: S0753-3322(24)01391-X. [Epub ahead of print]181 117505

Mitochondria in skeletal system-related diseases.

Liang Pei, Zhuo Yao, Dong Liang, Keda Yang, Lin Tao.

  Skeletal system-related diseases, such as osteoporosis, arthritis, osteosarcoma and sarcopenia, are becoming major public health concerns. These diseases are characterized by insidious progression, which seriously threatens patients' health and quality of life. Early diagnosis and prevention in high-risk populations can effectively prevent the deterioration of these patients. Mitochondria are essential organelles for maintaining the physiological activity of the skeletal system. Mitochondrial functions include contributing to the energy supply, modulating the Ca2+ concentration, maintaining redox balance and resisting the inflammatory response. They participate in the regulation of cellular behaviors and the responses of osteoblasts, osteoclasts, chondrocytes and myocytes to external stimuli. In this review, we describe the pathogenesis of skeletal system diseases, focusing on mitochondrial function. In addition to osteosarcoma, a characteristic of which is active mitochondrial metabolism, mitochondrial damage occurs during the development of other diseases. Impairment of mitochondria leads to an imbalance in osteogenesis and osteoclastogenesis in osteoporosis, cartilage degeneration and inflammatory infiltration in arthritis, and muscle atrophy and excitationcontraction coupling blockade in sarcopenia. Overactive mitochondrial metabolism promotes the proliferation and migration of osteosarcoma cells. The copy number of mitochondrial DNA and mitochondria-derived peptides can be potential biomarkers for the diagnosis of these disorders. High-risk factor detection combined with mitochondrial component detection contributes to the early detection of these diseases. Targeted mitochondrial intervention is an effective method for treating these patients. We analyzed skeletal system-related diseases from the perspective of mitochondria and provided new insights for their diagnosis, prevention and treatment by demonstrating the relationship between mitochondria and the skeletal system.

Keywords:  Mitochondria; Mitophagy; ROS; Skeletal system; TCA

DOI:  https://doi.org/10.1016/j.biopha.2024.117505
Methods Enzymol. 2024 ;pii: S0076-6879(24)00405-1. [Epub ahead of print]707 519-539

Analysis of mitochondrial biogenesis regulation by oxidative stress.

Dheeraj Pathak, Thanuja Krishnamoorthy, Naresh Babu V Sepuri.

  Of all the causes of metabolic and neurological disorders, oxidative stress distinguishes itself by its sweeping effect on the dynamic cellular redox homeostasis and, in its wake, exposing the vulnerabilities of the protein machinery of the cell. High levels of Reactive Oxygen Species (ROS) that mitochondria produce during ATP synthesis can damage mtDNA, lipids, and essential mitochondrial proteins. ROS majorly oxidizes cysteine and methionine amino acids in peptides, which can lead to protein unfolding or misfolding of proteins, which ultimately can have a toll on their function. As mitochondrial biogenesis relies on the continuous import of nuclear-encoded proteins into mitochondria mediated by mitochondrial protein import complexes, oxidative stress triggered by mitochondria can rapidly and detrimentally affect mitochondrial biogenesis and homeostasis. Functional Mge1 is a homodimer and acts as a cochaperone and a nucleotide exchange factor of mitochondrial heat shock protein 70 (mHsp70), crucial for mitochondrial protein import. Oxidative stress like ROS, oxidizes Met 155 in Mge1, compromising its ability to dimerize and interact with mHsp70. The cell employs Methionine sulphoxide reductase 2 (Mxr2), a member of the methionine sulphoxide reductase family, to reduce oxidized Met 155 and thereby restore the essential function of Mge1. Oxidation of methionine as a regulated post-translational modification has been gaining traction. Future high throughput studies that can scan the entire mitochondrial proteome to interrogate methionine oxidation and reversal may increase the repertoire of mitochondrial proteins undergoing regulated oxidation and reduction. In this chapter, we describe the methods followed in our laboratory to study the oxidation of Mge1 and its reduction by Mxr2 in vitro.

Keywords:  Cross linking; Methionine oxidation; Methionine sulfoixde reductase 2; Mge1; Mitochondria; Reactive Oxygen Species

DOI:  https://doi.org/10.1016/bs.mie.2024.07.060
Bratisl Lek Listy. 2024 ;125(11): 706-712

Mitochondrial oxidative stress in immunopathogenesis of diseases.

Juraj Deglovic, Marek Supler, Mario Dvorzak, Katarina Gazdikova.

Mitochondria are subcellular organelles involved in many metabolic events, including oxidative phosphorylation and signaling in tissue-specific processes. They play a key role in cell proliferation, differentiation and death.Diseases in the pathogenesis of which mitochondrial oxidative stress and immunity play a significant role include cancer, cardiovascular, nervous and rheumatic diseases as well as liver, lung and kidney diseases. In addition, mitochondria participate in the pathogenesis of infections and autoimmunity.Mitochondrial dysfunction can be positively influenced by administration of antioxidants, including coenzyme Q10 (Tab. 1, Fig. 5, Ref. 20). Text in PDF www.elis.sk Keywords: mitochondria, immunopathogenesis, bronchial asthma, chronic hepatitis C, reactive oxidative species, antioxidants, coenzyme Q10.

DOI: https://doi.org/10.4149/BLL_2024_107
Mitochondrion. 2024 Nov 04. pii: S1567-7249(24)00135-1. [Epub ahead of print] 101977

The multifaceted modulation of mitochondrial metabolism in tumorigenesis.

Rajendiran Keerthiga, Yafang Xie, Desheng Pei, Ailing Fu.

  Changes in mitochondrial metabolism produce a malignant transformation from normal cells to tumor cells. Mitochondrial metabolism, comprising bioenergetic metabolism, biosynthetic process, biomolecular decomposition, and metabolic signal conversion, obviously forms a unique sign in the process of tumorigenesis. Several oncometabolites produced by mitochondrial metabolism maintain tumor phenotype, which are recognized as tumor indicators. The mitochondrial metabolism synchronizes the metabolic and genetic outcome to the potent tumor microenvironmental signals, thereby further promoting tumor initiation. Moreover, the bioenergetic and biosynthetic metabolism within tumor mitochondria orchestrates dynamic contributions toward cancer progression and invasion. In this review, we describe the contribution of mitochondrial metabolism in tumorigenesis through shaping several hallmarks such as microenvironment modulation, plasticity, mitochondrial calcium, mitochondrial dynamics, and epithelial-mesenchymal transition. The review will provide a new insight into the abnormal mitochondrial metabolism in tumorigenesis, which will be conducive to tumor prevention and therapy through targeting tumor mitochondria.

Keywords:  EMT-MET transition; OXPHOS; Oncometabolites; Plasticity; TCA cycle; Tumorigenesis

DOI:  https://doi.org/10.1016/j.mito.2024.101977
Mitochondrion. 2024 Nov 04. pii: S1567-7249(24)00137-5. [Epub ahead of print] 101979

Scientific investigation of non-coding RNAs in mitochondrial epigenetic and aging disorders: Current nanoengineered approaches for their therapeutic improvement.

Vaibhav Patange, Kailash Ahirwar, Tripti Tripathi, Pratima Tripathi, Rahul Shukla.

  Genetic control is vital for the growth of cells and tissues, and it also helps living things, from single-celled organisms to complex creatures, maintain a stable internal environment. Within cells, structures called mitochondria act like tiny power plants, producing energy and keeping the cell balanced. The two primary categories of RNA are messenger RNA (mRNA) and non-coding RNA (ncRNA). mRNA carries the instructions for building proteins, while ncRNA does various jobs at the RNA level. There are different kinds of ncRNA, each with a specific role. Some help put RNA molecules together correctly, while others modify other RNAs or cut them into smaller pieces. Still others control how much protein is made from a gene. Scientists have recently discovered many more ncRNAs than previously known, and their functions are still being explored. This article analyzes the RNA molecules present within mitochondria, which have a crucial purpose in the operation of mitochondria. We'll also discuss how genes can be turned on and off without changing their DNA code, and how this process might be linked to mitochondrial RNA. Finally, we'll explore how scientists are using engineered particles to silence genes and develop new treatments based on manipulating ncRNA.

Keywords:  Mitochondrial epigenetics; Neurodegeneration; Non-coding RNA; Transcriptomics; lnc-RNA; miRNA

DOI:  https://doi.org/10.1016/j.mito.2024.101979
Cell Calcium. 2024 Oct 23. pii: S0143-4160(24)00120-9. [Epub ahead of print]124 102962

Does a transmembrane sodium gradient control membrane potential in mammalian mitochondria?

David G Nicholls.

  In a recent publication, Hernansanz-Agusti̒n et al. propose that a sodium gradient across the inner mitochondrial membrane, generated by a Na+/H+ activity integral to Complex I can account for half of the mitochondrial membrane potential. This conflicts with conventional electrophysiological and chemiosmotic understanding.

Keywords:  Calcium signaling; Goldman equation; Membrane potential; Mitochondria; Sodium proton exchange

DOI:  https://doi.org/10.1016/j.ceca.2024.102962