Clinical Bioenergetics: From Pathophysiology to Clinical Translation

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CLINICAL BIOENERGETICS
CLINICAL BIOENERGETICS
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Contents
Contributors
Preface
	References
Acknowledgments
I - Foundational aspects of bioenergetics and disease
	1 - Tissue specificity of energy metabolism in mitochondria
		Introduction
			Mitochondria and the oxidative phosphorylation system
		Energetic metabolic profile of tissues and cell types
			Liver
			Heart
			Skeletal muscle
			Brain
			Adipose tissue
			Kidney
			Cancer cells
		Mitochondrial heterogeneity and tissue-specific properties of mitochondria
			Tissue-specific mitochondrial pathways
				Liver
				Brown adipose tissue
				Brain
				Kidney
			Tissue-specific differences in mitochondrial mass
			Tissue-specific differences in mitochondrial composition
				Tissue-specific composition of oxidative phosphorylation complexes and adenine nucleotide translocase
					Complex IV
					Complex V
					Adenine nucleotide translocator
				The mitochondrial proteome
				The mitochondrial lipidome
				Supercomplex organization
		Regulation of mitochondrial biogenesis and degradation
			Mitochondrial biogenesis
				Nuclear gene expression
					Skeletal muscle
					Liver
					Heart
					Adipose tissues
					Brain
				Mitochondrial gene expression
			Mitochondrial dynamics and degradation
		Conclusions and perspectives
		Acknowledgments
		References
	2 - Impaired mitochondrial bioenergetics and signaling pathways: an overview
		Introduction
		Mitochondria—structure and functions
		Electron transport chain
		Mitochondrial bioenergetics
		Signaling pathways
			Mitochondrial cytochrome c release regulates signaling pathway
			Hypoxic gene expression pathway
			cAMP pathway
		Impaired mitochondrial bioenergetics and signaling pathways
			Cancer
			Neurodegenerative disease
		Conclusion and future perspectives
		References
II - Disease-specific case studies
	3 - Abnormal mitochondrial metabolism in obesity and insulin resistance
		Introduction
		Abnormal mitochondrial metabolism in obesity and insulin resistance
		Conclusion
		References
	4 - Impaired mitochondrial energy metabolism: etiologies and implications in neurodegenerative disease
		Introduction
		Mitochondrial bioenergetics measurement parameters
			Basal respiration
			Proton leak assay
			Coupling efficiency and reserve respiratory capacity
			Respiratory control and nonmitochondrial respiration
		Mechanisms of impaired mitochondrial metabolism
		Intrinsic factors
			Mutations in mitochondrial/nuclear DNA affecting oxidative phosphorylation
		Ca++ imbalance
		Intracellular reactive oxygen species
		Extrinsic factors
			Dysregulation of metal ions
			Mitochondrial inhibitors and toxins
			Environmental organic pollutants
			Environmental mitochondrial toxicants
			Fat-rich or ketogenic diet
		Impaired mitochondrial metabolism and neurodegenerative disease
			Alzheimer's disease
			Huntington's disease
			Parkinson's disease
			Amyotrophic lateral sclerosis
			Future directions
		Conclusions
		References
	5 - Mitochondrial dysfunction in kidney diseases
		Key points
		Introduction
			Mitochondrial energetic metabolism in kidney development
			Mitochondrial etiologies can directly trigger kidney disease
			Mitochondrial oxidative stress
			Mitochondrial dynamics
			Mitochondrial biogenesis
			Mitophagy
			Coordination of mitochondrial dynamics, localization, and trafficking
			Mitochondrial calcium handling
			Noncoding RNAs and mitochondrial remodeling
			Renal cell carcinoma and mitochondria and one-carbon metabolism
		Conclusion and perspective
		Conflict of interest
		References
	6 - Mitochondrial role in NAFLD as a chronic disease
		Nonalcoholic fatty liver disease essentials
			Is nonalcoholic fatty liver disease a mitochondrial disease?
		Nonalcoholic fatty liver disease lipid overload: mitochondrial status
		Mitochondrial dysfunction
			Oxidative stress (reactive oxygen species production)
			Antioxidants
		Mitochondrial dynamics
			Mitophagy in nonalcoholic fatty liver disease
		Mitochondrial DNA, role in nonalcoholic fatty liver disease
		Conclusion remarks
		References
	7 - Decreased bioenergetics in traumatic brain injury
		Introduction
		Classifications and diagnosis of traumatic brain injury
		Oxidative stress and traumatic brain injury
		Traumatic brain injury and dementia
		Traumatic brain injury and its correlation to aggression
		Traumatic brain injury and posttraumatic stress disorder
		Concussive brain injuries
		Reduced energy metabolism associated with mild and moderate traumatic brain injury
		Glutamate excitotoxicity and traumatic brain injury
		Calcium and traumatic brain injury
		Reduced energetics associated with severe traumatic brain injury
			Mitochondrial matrix proteins
				Hexokinase
				Phosphofructokinase
				Phosphoglycerate kinase
				Pyruvate dehydrogenase complex
				Glutamate dehydrogenase
		Inner mitochondrial membrane
			Complex I—NADH dehydrogenase
			Complex II—succinate dehydrogenase complex
			Complex IV—cytochrome c oxidase
		Peripheral dysfunction associated with traumatic brain injury
			Hepatic dysfunction and traumatic brain injury
			Arginase and nitric oxide synthase dysfunction
		Treatment strategies for traumatic brain injury
		Conclusions
		References
	8 - Impaired mitochondrial bioenergetics in psychiatric disorders
		Introduction
		Mitochondrial functions and links to psychiatric disorders—bioenergetics and adenosine triphosphate production
		Mitochondrial functions and links to psychiatric disorders—calcium homeostasis
		Mitochondrial functions and links to psychiatric disorders—apoptosis
		Mitochondrial functions and links to psychiatric disorders—synaptic plasticity
		Genetic evidence for mitochondrial involvement in major depression
		Genetic evidence for mitochondrial involvement in bipolar disorder
		Genetic evidence for mitochondrial involvement in schizophrenia
			A critical view of mitochondrial etiology in psychiatric disorders
		Conclusions
		References
III - Modes of analysis in clinical bioenergetics
	9 - Monitoring mitochondrial oxygenation in clinical environment
		Introduction
		Rationale
		Background
			Oxygen
			Quantifying dissolved oxygen
			Porphyrins
			Measuring oxygen with porphyrins
			Protoporphyrin IX
		Measuring mitoPO2
			Enhancing mitochondrial protoporphyrin IX
			Routes of aminolevulinic acid administration
			Oxygen-dependent delayed fluorescence
			From lifetime to PO2
			Basic setup
		Measuring mitochondrial oxygen consumption
		The COMET measuring system
		Clinical examples
			Monitoring mitoPO2
			Mitochondrial health
		Next steps
		Conclusion
		Acknowledgements
		References
	10 - Assessing metabolic flexibility and mitochondrial bioenergetics
		Historical perspective
		Mitochondria, over a-billion-year-old organelle
		Mitochondrial function and metabolic flexibility
		Mitochondrial dysfunction and metabolic flexibility in diabetes
		Mitochondrial dysfunction in cardiovascular disease
		Mitochondrial dysfunction and Alzheimer's disease
		Mitochondrial bioenergetics in cancer
		Mitochondrial function and aging
		Causes of mitochondrial dysfunction
		Mitochondrial function assessment
		Indirect methodology to assess mitochondrial function and metabolic flexibility
		Assessing mitochondrial function and metabolic flexibility for exercise prescription
		Future directions
		References
	11 - Assessing the real-time metabolism and bioenergetics of single cells using fluorescence biosensors
		Introduction
		Cellular metabolism
			Adenosine triphosphate production
			Mitochondria as adenosine triphosphate consumers
		Methods to study cellular metabolism and bioenergetics
			Metabolic inhibitors
			Cell-based assays and molecular probes
		Fluorescent biosensors
		Measurement of adenosine triphosphate levels inside single living cells
		Measurement of ATP: ADP ratio inside single living cells
			Visualization of nucleotides within cellular compartments
		Challenges for using genetically encoded fluorescent biosensors
		Summary
		References
	12 - Bioenergetic profiling in the skin
		Introduction
			Skin structure and function
				Epidermis
				Dermis
			Environmental insults affecting the skin
		In vitro models for the assessment of bioenergetic alterations
			Bioenergetic alterations evaluated on cell lines and primary culture
			Use of 3D skin culture to analyze bioenergetic alterations
		In vivo models for skin bioenergetics evaluation
			Bioenergetic parameters evaluated on subcellular fractions
			Bioenergetic evaluation on skin single-cell suspension
			Other in vivo approaches to cellular bioenergetics evaluation
		Conclusions
		References
	13 - Evaluating tissue bioenergetics by phosphorous-31 magnetic resonance spectroscopy
		Introduction
		Physical principles of magnetic resonance spectroscopy
			Magnetic resonance signal and magnetic resonance–detectable nuclei
			Chemical shift
			Characteristics of magnetic resonance spectra
		Phosphorus-31 MRS
			Quantification of metabolite concentrations
			Measurement of intracellular pH
			Evaluation of mitochondrial oxidative capacity by dynamic 31P-MRS
			Measuring rate of ATP synthesis by magnetization transfer
		Conclusions
		References
	14 - Targeting respiratory complex I—molecular mechanism and drug design
		Background
		Computational enzymology and drug design
		Structure and mechanism of complex I
		Q-binding sites in the Q tunnel
		Reactive oxygen species production in complex I and its physiologically relevant states
		Complex I targeting compounds—some examples
		Drug design strategies for complex I
		Acknowledgments
		References
IV - Theraputic opportunities for impaired bioenergetics
	15 - Targeting Alzheimer's disease neuronal mitochondria as a therapeutic approach
		Introduction
		The mitochondrion
		Mitochondria in Alzheimer's disease
		Cellular therapy
		Intercellular mitochondrial transplantation
		Editing mtDNA mutations
		Enhancing mitochondrial biogenesis
		Targeting reactive oxygen species
		Mitophagy
		Mitochondria the proteasome
		Targeting mitochondrial fission
		Mitochondria and the inflammasome
		Bypassing respiratory complexes defects using xenogenes
		Alternate energy sources
		Ketogenic diet
		Calorie restriction
		Endurance exercise
		Mitochondrial cholesterol
		Mild mitochondrial uncoupling
		Mitochondrial membrane potential
		Photobiomodulation
		Acknowledgments
		Conflicts of interest
		References
	16 - Mitochondria replacement as an innovative treatment to tackle impaired bioenergetics in clinical medicine
		Introduction
			Mitochondria and mitochondrial DNA in oocytes or in early embryos
			Current reproductive option for inherited mitochondrial diseases
			Mitochondrial replacement therapy
		Safety of mitochondrial replacement therapy and potential application in future assisted reproductive technology
		Conclusion
		Acknowledgment
		References
	17 - Mitochondrial drug delivery systems: therapeutic application for clinical bioenergetics in neurodegenerative d ...
		Introduction
		Importance of mitochondrial function in the brain
			Mitochondrial Ca2+ regulation and homeostasis
			Mitochondria-induced free radicals and oxidative stress
			Mitochondrial dynamics
		Signatures of mitochondrial dysfunction in neurodegenerative disease
			Alzheimer's disease
			Parkinson's disease
			Huntington's disease
			Traumatic brain injury
		Mitochondrial-directed drug delivery for neurodegenerative disease
			Targeting mitochondrial membrane potential
			Targeting mitochondrial permeability transition pore and mitochondrial-induced apoptosis
			Targeting biofuel deficiency
			Targeting oxidative stress
			Targeting mitochondrial dynamics
		Closing remarks
		References
	18 - Dietary interventions for patients with obesity and impaired bioenergetics
		Introduction
		Impaired bioenergetics in obesity
		Effectiveness of dietary interventions in weight loss
		Dietary treatment program recommendations
			Determine patient energy requirements
			Estimate realistic goals of weight reduction or other health-related variables
			Select an adapted dietary pattern
			Schedule continuous visits
		References
	19 - Novel nutraceuticals to tackle brain and muscle bioenergetics
		Nicotinamide adenine dinucleotide
		Acetyl-l-carnitine
		α-Ketoglutarate
		Succinate
		Creatine and creatine analogs
		Citicoline
		Medium-chain triglycerides
		Quercetin
		Resveratrol
		Coenzyme Q10
		Other nutraceuticals
		Conclusion
		References
	20 - Therapeutic targeting of cardiolipin composition in injury and disease using TPP-conjugated compounds
		Cardiolipin synthesis
			Cardiolipin: a mitochondrial inner membrane lipid
			Cardiolipin fatty acyl composition and biosynthesis
			Cardiolipin remodeling
		Cardiolipin and mitochondrial function
		Cardiolipin and mitochondrial morphology
		Cardiolipin in mitochondrial disease and dysfunction
			Changes in cardiolipin content and composition
				The role of cardiolipin in apoptosis
				The role of cardiolipin in ischemia–reperfusion injury
				The role of cardiolipin in cardioskeletal muscular dysfunction
		Mitochondrial-targeted therapeutic approaches to cardiolipin
			Mitochondrial targeting
			Triphenylphosphonium: a mitochondrial-targeting moiety
		Applications of triphenylphosphonium-conjugated compounds
			Mitochondrially targeted antioxidants: MitoQ, MitoE2, and more
		Triphenylphosphonium conjugation to manipulate cardiolipin
			TPP-LA: a potential therapeutic agent for Barth syndrome
			Synthesis of triphenylphosphonium-conjugated compounds
		Conclusions and future perspectives
		References
	21 - NEET proteins as novel drug targets for mitochondrial dysfunction
		Introduction
			Involvement of NEET proteins in different diseases
			Structure and [2Fe-2S] cluster lability of NEET proteins
			Lability of the NEET [2Fe–2S] clusters and their involvement in different diseases
			Ligands/drugs of NEET proteins
		Conclusion
		Acknowledgments
		References
	22 - Translation of bioenergetics therapies: challenges from bench to bedside
		Introduction
		Mitochondria components and functions
		Mitochondrial DNA
		Reactive oxygen species in mitochondria
		Mitochondrial bioenergetics
		Impaired mitochondrial bioenergetics in health and disease
		Mitochondrial medicine
		Bioenergetic therapy in neurodegenerative diseases
		Coenzyme Q10
		MitoQ
		MitoVitE
		MitoPBN
		Creatine
		Lifestyle interventions
		Bioenergetic therapy in cancer
		Conclusions and future prospective
		References
	23 - New therapeutics to modulate mitochondrial energy metabolism in neurodegenerative disorders: the example of mi ...
		Introduction
		Treating mitochondrial dysfunction
		Treating oxidative stress
		Treating coenzyme Q10 deficiencies
		Treating Leber optic neuropathy with idebenone
		Treating mitochondrial neurogastrointestinal encephalomyopathy
		Treating mitochondrial disorders: innovative strategies
		Treating mitochondrial disorders: gene and germline therapy
		Treating mitochondrial encephalopathy with lactic acidosis and strokelike episodes
		Treating mitochondrial epilepsy and myoclonus
		Treating other CNS features
		Preventing drug toxicity
		Treating persons with mitochondrial disorder
		Treating “Conventional” neurodegenerative disorders?
		References
	24 - Targeting impaired bioenergetics in heart failure
		Introduction
		Posttranslational modifications of mitochondrial proteins underlie bioenergetic dysfunction in heart failure
			CoQ10 in heart failure
			Cardiolipin support of inner mitochondrial membrane integrity and function
			Pyruvate dehydrogenase complex and metabolic remodeling
			Protein acetylation and regulation of oxidative phosphorylation
			Mitochondrial transplantation
		Conclusion
		Acknowledgments
		References
	25 - Exploring vulnerabilities of quiescent tumor cells by targeting mitochondrial bioenergetics
		Introduction
		The microenvironment of solid tumors results in metabolic vulnerabilities
		Mitochondrial inhibitors as cancer therapeutics
		ADME aspects of mitochondrial inhibitors
		Biomarkers
		Acknowledgments
		References
	26 - Modulation of the mitochondrial function with polyphenols and other natural bioactive compounds to treat obesity
		Introduction
		Obesity and mitochondria
		Bioactive compounds for obesity treatment by mitochondria modulation
			Polyphenols
				Polyphenol compounds classification
				Polyphenol effects on obesity by mitochondria modulation
					Resveratrol
					Resveratrol
					Resveratrol
					EGCG and tea catechins
					Curcumin
					Anthocyanins
					Proanthocyanidins and other flavanols
					Quercetin
					Naringin
					Sesamol
			Other food bioactive compounds
				Polyunsaturated fatty acids
				Amino acids
				Retinoids
				Berberine
				Butyrate
				Fucoxanthin
				Probiotics
				Capsaicinoids
				Miscellany
		Conclusions
		References
	27 - Antioxidants and natural-derived products in the modulation of mitochondrial bioenergetics and dysfunction in  ...
		Introduction
		Renal mitochondrial bioenergetics alterations in chronic kidney disease
		Mitochondrial oxidative stress and its role on chronic kidney disease progression
		Natural compounds and mitochondria-targeting therapeutics
			Mitochondrial-targeting antioxidants
				MitoQ
				CoQ10
				Mito-TEMPO
				SS-31
			Peptide-derived compounds
				l-carnitine
				Tmem126b
				Melatonin
			Dietary polyphenols
				Resveratrol
				Curcumin
				Procyanidin B2
			Plant-derived functional extractions
			Fatty acid–derived compounds
				Eicosapentaenoic acid
				α-Lipoic acid
		Conclusion
		Acknowledgements
		References
	28 - Transcranial and systemic photobiomodulation for the enhancement of mitochondrial metabolism in depression
		Mitochondrial mechanisms of photobiomodulation
		Effects of photobiomodulation on major depressive disorder relevant mechanisms
		Neurophysiological mechanisms of photobiomodulation on major depressive disorder
		Antidepressant effect of transcranial photobiomodulation
			Preclinical studies
			Clinical studies on transcranial photobiomodulation
			Clinical studies on systemic photobiomodulation
			Safety and tolerability
			Future directions
		References
	29 - Alterations in mitochondrial glucose carbon metabolism in epilepsy and targeted metabolic treatments
		Introduction
			Epilepsy
			Epilepsy models
				Chronic epilepsy models
				Acute seizure models
			Glucose metabolism is needed for the healthy brain
		Glucose metabolism
			Glucose uptake and cytosolic metabolism
			The tricarboxylic acid cycle and oxidative phosphorylation
			Anaplerosis—refilling of the (deficient) tricarboxylic acid cycle intermediate pool
		Interictal changes in cytosolic glucose metabolism and lactate
		Mitochondrial impairments in glucose metabolism, the electron transport chain and the need for anaplerosis
			Pyruvate dehydrogenase
			Other tricarboxylic acid cycle and related enzymes
			Electron transport chain
			Summary of mitochondrial metabolic impairments in epilepsy
		Therapies targeting mitochondrial metabolism for the treatment of epilepsy
			Pyruvate, oxaloacetate, and α-ketoglutarate
			Even medium-chain triglycerides
			Triheptanoin—an uneven medium-chain triglyceride
			Clinical trials of medium-chain triglycerides and triheptanoin
		Summary and conclusion
		References
	Index
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