Mitochondrial dynamism and heart disease: Changing shape and shaping change

Mitochondria of adult cardiomyocytes appear hypo-dynamic, lacking interconnected reticular networks and the continual fission and fusion observed in many other cell types. Nevertheless, proteins essential to mitochondrial network remodeling are abundant in adult hearts. Recent findings from cardiac-specific ablation of mitochondrial fission and fusion protein genes have revealed unexpected roles for mitochondrial dynamics factors in mitophagic mitochondrial quality control. This overview examines the clinical and experimental evidence for and against a meaningful role for the mitochondrial dynamism–quality control interactome in normal and diseased hearts. Newly discovered functions of mitochondrial dynamics factors in maintaining optimal cardiac mitochondrial fitness suggest that deep interrogation of clinical cardiomyopathy is likely to reveal genetic variants that cause or modify cardiac disease through their effects on mitochondrial fission, fusion, and mitophagy

Mechanisms of non-apoptotic programmed cell death in diabetes and heart failure

Programmed cell elimination is an important pathological mediator of disease. Multiple pathways to programmed cell death have been delineated, including apoptosis, autophagy and programmed necrosis. Cross-talk between the signaling pathways mediating each process has made it difficult to define specific mechanisms of in vivo programmed cell death. For this reason, many “apoptotic” diseases may involve other death signaling pathways. Recent advances in genetic complementation using mouse knockout models are helping to dissect apoptotic and necrotic cell death in different pathological states. The current state of research in this area is reviewed, focusing upon new findings describing the role of programmed necrosis induced by the mitochondrial permeability transition in mouse models of heart failure and diabetes

Reversing dysdynamism to interrupt mitochondrial degeneration in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is one of several chronic neurodegenerative conditions in which mitochondrial abnormalities are posited to contribute to disease progression. Therapeutic options targeting mitochondria include enhancing metabolism, suppressing reactive oxygen production and disrupting mitochondria-mediated programmed cell death pathways. Herein is reviewed mechanistic evidence supporting a meaningful pathophysiological role for the constellation of abnormal mitochondrial fusion, fission and transport, collectively designated mitochondrial dysdynamism, in ALS. Following this is a discussion on preclinical studies in ALS mice that seemingly validate the idea that normalizing mitochondrial dynamism can delay ALS by interrupting a vicious cycle of mitochondrial degeneration, leading to neuronal die-back and death. Finally, the relative benefits of suppressing mitochondrial fusion vs. enhancing mitochondrial fusion in ALS are speculated upon, and the paper concludes with the prediction that the two approaches could be additive or synergistic, although a side-by-side comparative trial may be challenging to perform

Mitofusin 2 dysfunction and disease in mice and men

A causal relationship between Mitofusin (MFN) 2 gene mutations and the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2A (CMT2A) was described over 15 years ago. During the intervening period much has been learned about MFN2 functioning in mitochondrial fusion, calcium signaling, and quality control, and the consequences of these MFN2 activities on cell metabolism, fitness, and development. Nevertheless, the challenge of defining the central underlying mechanism(s) linking mitochondrial abnormalities to progressive dying-back of peripheral arm and leg nerves in CMT2A is largely unmet. Here, a different perspective of why, in humans, MFN2 dysfunction preferentially impacts peripheral nerves is provided based on recent insights into its role in determining whether individual mitochondria will be fusion-competent and retained within the cell, or are fusion-impaired, sequestered, and eliminated by mitophagy. Evidence for and against a regulatory role of mitofusins in mitochondrial transport is reviewed, nagging questions defined, and implications on mitochondrial fusion, quality control, and neuronal degeneration discussed. Finally, in the context of recently described mitofusin activating peptides and small molecules, an overview is provided of potential therapeutic applications for pharmacological enhancement of mitochondrial fusion and motility in CMT2A and other neurodegenerative conditions

Predicting mitochondrial dynamic behavior in genetically defined neurodegenerative diseases

Mitochondrial dynamics encompass mitochondrial fusion, fission, and movement. Mitochondrial fission and fusion are seemingly ubiquitous, whereas mitochondrial movement is especially important for organelle transport through neuronal axons. Here, we review the roles of different mitochondrial dynamic processes in mitochondrial quantity and quality control, emphasizing their impact on the neurological system in Charcot-Marie-Tooth disease type 2A, amyotrophic lateral sclerosis, Friedrich\u27s ataxia, dominant optic atrophy, and Alzheimer\u27s, Huntington\u27s, and Parkinson\u27s diseases. In addition to mechanisms and concepts, we explore in detail different technical approaches for measuring mitochondrial dynamic dysfunction in vitro, describe how results from tissue culture studies may be applied to a better understanding of mitochondrial dysdynamism in human neurodegenerative diseases, and suggest how this experimental platform can be used to evaluate candidate therapeutics in different diseases or in individual patients sharing the same clinical diagnosis

Genomic context differs between human dilated cardiomyopathy and hypertrophic cardiomyopathy

Background Inherited cardiomyopathies display variable penetrance and expression, and a component of phenotypic variation is genetically determined. To evaluate the genetic contribution to this variable expression, we compared protein coding variation in the genomes of those with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Methods and Results Nonsynonymous single-nucleotide variants (nsSNVs) were ascertained using whole genome sequencing from familial cases of HCM (n=56) or DCM (n=70) and correlated with echocardiographic information. Focusing on nsSNVs in 102 genes linked to inherited cardiomyopathies, we correlated the number of nsSNVs per person with left ventricular measurements. Principal component analysis and generalized linear models were applied to identify the probability of cardiomyopathy type as it related to the number of nsSNVs in cardiomyopathy genes. The probability of having DCM significantly increased as the number of cardiomyopathy gene nsSNVs per person increased. The increase in nsSNVs in cardiomyopathy genes significantly associated with reduced left ventricular ejection fraction and increased left ventricular diameter for individuals carrying a DCM diagnosis, but not for those with HCM. Resampling was used to identify genes with aberrant cumulative allele frequencies, identifying potential modifier genes for cardiomyopathy. Conclusions Participants with DCM had more nsSNVs per person in cardiomyopathy genes than participants with HCM. The nsSNV burden in cardiomyopathy genes did not correlate with the probability or manifestation of left ventricular measures in HCM. These findings support the concept that increased variation in cardiomyopathy genes creates a genetic background that predisposes to DCM and increased disease severity

Mitochondrial biogenesis and dynamics in the developing and diseased heart

The mitochondrion is a complex organelle that serves essential roles in energy transduction, ATP production, and a myriad of cellular signaling events. A finely tuned regulatory network orchestrates the biogenesis, maintenance, and turnover of mitochondria. The high-capacity mitochondrial system in the heart is regulated in a dynamic way to generate and consume enormous amounts of ATP in order to support the constant pumping function in the context of changing energy demands. This review describes the regulatory circuitry and downstream events involved in mitochondrial biogenesis and its coordination with mitochondrial dynamics in developing and diseased hearts

Piperine derivatives enhance fusion and axonal transport of mitochondria by activating mitofusins

Piperine (1-piperoylpiperidine) is the major pungent component of black pepper (Piper nigrum) and exhibits a spectrum of pharmacological activities. The molecular bases for many of piperine’s biological effects are incompletely defined. We noted that the chemical structure of piperine generally conforms to a pharmacophore model for small bioactive molecules that activate mitofusin (MFN)-mediated mitochondrial fusion. Piperine, but not its isomer chavicine, stimulated mitochondrial fusion in MFN-deficient cells with EC50 of ~8 nM. We synthesized piperine analogs having structural features predicted to optimize mitofusin activation and defined structure-activity relationships (SAR) in live-cell mitochondrial elongation assays. When optimal spacing was maintained between amide and aromatic groups the derivatives were potent mitofusin activators. Compared to the prototype phenylhexanamide mitofusin activator, 2, novel molecules containing the piperidine structure of piperine exhibited markedly enhanced passive membrane permeability with no loss of fusogenic potency. Lead compounds 5 and 8 enhanced mitochondrial motility in cultured murine Charcot-Marie-Tooth disease type 2A (CMT2A) neurons, but only 8 improved mitochondrial transport in sciatic nerve axons of CMT2A mice. Piperine analogs represent a new chemical class of mitofusin activators with potential pharmaceutical advantages

Mitochondrial phenotypes in genetically diverse neurodegenerative diseases and their response to mitofusin activation

Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patients with genetic neurodegenerative diseases often exhibit mitochondrial fragmentation, reflecting an imbalance in mitochondrial fusion and fission (mitochondrial dysdynamism). Charcot-Marie-Tooth (CMT) disease type 2A is the prototypical disorder of impaired mitochondrial fusion caused by mutations in the fusion protein mitofusin (MFN)2. Yet, cultured CMT2A patient fibroblast mitochondria are often reported as morphologically normal. Metabolic stress might evoke pathological mitochondrial phenotypes in cultured patient fibroblasts, providing a platform for the pre-clinical individualized evaluation of investigational therapeutics. Here, substitution of galactose for glucose in culture media was used to redirect CMT2A patient fibroblasts (MFN2 T105M, R274W, H361Y, R364W) from glycolytic metabolism to mitochondrial oxidative phosphorylation, which provoked characteristic mitochondrial fragmentation and depolarization and induced a distinct transcriptional signature. Pharmacological MFN activation of metabolically reprogrammed fibroblasts partially reversed the mitochondrial abnormalities in CMT2A and CMT1 and a subset of Parkinson\u27s and Alzheimer\u27s disease patients, implicating addressable mitochondrial dysdynamism in these illnesses