Three-dimensional electron microscopy techniques for unravelling mitochondrial dysfunction in heart failure and identification of new pharmacological targets

British Journal of Pharmacology
Hussam M DaghistaniAshraf Kitmitto

Abstract

A hallmark of heart failure is mitochondrial dysfunction leading to a bioenergetics imbalance in the myocardium. Consequently, there is much interest in targeting mitochondrial abnormalities to attenuate the pathogenesis of heart failure. This review discusses (i) how electron microscopy (EM) techniques have been fundamental for the current understanding of mitochondrial structure-function, (ii) the paradigm shift in resolutions now achievable by 3-D EM techniques due to the introduction of direct detection devices and phase plate technology, and (iii) the application of EM for unravelling mitochondrial pathological remodelling in heart failure. We further consider the tremendous potential of multi-scale EM techniques for the development of therapeutics, structure-based ligand design and for delineating how a drug elicits nanostructural effects at the molecular, organelle and cellular levels. In conclusion, 3-D EM techniques have entered a new era of structural biology and are poised to play a pivotal role in discovering new therapies targeting mitochondria for treating heart failure. LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translati...Continue Reading

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Citations

Feb 6, 2020·Biological Reviews of the Cambridge Philosophical Society·Kyle B Heine, Wendy R Hood
Dec 4, 2019·British Journal of Pharmacology·Xin WangMichelangelo Campanella
Jun 20, 2020·Stem Cell Reviews and Reports·Rahele A FarahaniAlfonso Eirin

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Methods Mentioned

BETA
scanning electron microscopy
transgenic
biopsy
transmission electron microscopy
NMR
X‐ray
GTPases
GTPase
transfection
confocal microscopy

Software Mentioned

SPA
RELION
SEM
UCSF Chimera
IMOD
MotionCor2
FIB

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