Neurodegenerative proteinopathies are a group of pathologically similar, progressive disorders of the nervous system, characterised by structural alterations within and toxic misfolding of susceptible proteins. Oligomerisation of Aβ, tau, α-synuclein and TDP-43 leads to a toxin gain- or loss-of-function contributing to the phenotype observed in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia. Misfolded proteins can adversely affect mitochondria, and post-mitotic neurones are especially sensitive to metabolic dysfunction. Misfolded proteins impair mitochondrial dynamics (morphology and trafficking), preventing functional mitochondria reaching the synapse, the primary site of ATP utilisation. Furthermore, a direct association of misfolded proteins with mitochondria may precipitate or augment dysfunctional oxidative phosphorylation and mitochondrial quality control, causing redox dyshomeostasis observed in disease. As such, a significant interest lies in understanding mechanisms of mitochondrial toxicity in neurodegenerative disorders and in dissecting these mechanisms with a view of maintaining mitochondrial homeostasis in disease. Recent advances in understanding mitochondrially controlled cell death pathways and elucidating the mitochondrial permeability pore bioarchitecture are beginning to present new avenues to target neurodegeneration. Novel mitochondrial roles of deubiquitinating enzymes are coming to light and present an opportunity for a new class of proteins to target therapeutically with the aim of promoting mitophagy and the ubiquitin–proteasome system. The brain is enormously metabolically active, placing a large emphasis on maintaining ATP supply. Therefore, identifying mechanisms to sustain mitochondrial function may represent a common intervention point across all proteinopathies.

The platelet is considered as an accessible and valuable tool to study mitochondrial function, owing to its greater content of fully functional mitochondria compared with other metabolically active organelles. Different lines of studies have demonstrated that mitochondria in platelets have function far more than thrombogenesis regulation, and beyond hemostasis, platelet mitochondrial dysfunction has also been used for studying mitochondrial-related diseases. In this review, the interplay between platelet mitochondrial dysfunction and oxidative stress, mitochondrial DNA lesions, electron transfer chain impairments, mitochondrial apoptosis and mitophagy has been outlined. Meanwhile, considerable efforts have been made towards understanding the role of platelet mitochondrial dysfunction in human diseases, such as diabetes mellitus, sepsis and neurodegenerative disorders. Alongside this, we have also articulated our perspectives on the development of potential biomarkers of platelet mitochondrial dysfunction in mitochondrial-related diseases.

One in 400 people has a maternally inherited mutation in mtDNA potentially causing incurable disease. In so-called heteroplasmic disease, mutant and normal mtDNA co-exist in the cells of carrier women. Disease severity depends on the proportion of inherited abnormal mtDNA molecules. Families who have had a child die of severe, maternally inherited mtDNA disease need reliable information on the risk of recurrence in future pregnancies. However, prenatal diagnosis and even estimates of risk are fraught with uncertainty because of the complex and stochastic dynamics of heteroplasmy. These complications include an mtDNA bottleneck, whereby hard-to-predict fluctuations in the proportions of mutant and normal mtDNA may arise between generations. In ‘mitochondrial replacement therapy’ (MRT), damaged mitochondria are replaced with healthy ones in early human development, using nuclear transfer. We are developing non-invasive alternatives, notably activating autophagy, a cellular quality control mechanism, in which damaged cellular components are engulfed by autophagosomes. This approach could be used in combination with MRT or with the regular management, pre-implantation genetic diagnosis (PGD). Mathematical theory, supported by recent experiments, suggests that this strategy may be fruitful in controlling heteroplasmy. Using mice that are transgenic for fluorescent LC3 (the hallmark of autophagy) we quantified autophagosomes in cleavage stage embryos. We confirmed that the autophagosome count peaks in four-cell embryos and this correlates with a drop in the mtDNA content of the whole embryo. This suggests removal by mitophagy (mitochondria-specific autophagy). We suggest that modulating heteroplasmy by activating mitophagy may be a useful complement to mitochondrial replacement therapy.

Mitochondrial dysfunction is a hallmark of both idiopathic and familial Parkinson's disease (PD). Mutations in the PARK2 and PARK6 genes, coding for the cytosolic E3 ubiquitin protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1 [phosphatase and tensin homologue (PTEN)-induced putative kinase 1], lead to clinically similar early-onset Parkinsonian syndromes. PINK1 and Parkin cooperate within a conserved pathway to preserve mitochondrial quality through the regulation of a variety of processes, including mitochondrial dynamics, transport, bioenergetics, biogenesis and turnover. The molecular mechanisms behind the orchestration of this plethora of functions remain poorly understood. In the present review, we emphasize the functional overlap between the PINK1–Parkin pathway and the endoplasmic reticulum (ER)-mitochondria interface, a subcellular compartment critically involved in neurodegeneration. We discuss how this compartment may constitute a hub for the spatiotemporal organization of the activities of the PINK1–Parkin pathway.

Defects of mitochondrial functions have been implicated in many different human diseases, in particular neurodegenerative diseases. The kinase PINK1 [phosphatase and tensin homologue (PTEN)-induced kinase 1] has been identified as a crucial player in a specific damage signalling pathway, eliminating defective mitochondria by an autophagic process. Mutations in PINK1 have been shown to cause familial cases of Parkinson's disease. In this review, we summarize the biochemical mechanisms that underlie the association of PINK1 with mitochondria under normal and pathological conditions. This unconventional mitochondrial localization pathway is discussed in the context of the role of PINK1 as a sensor of mitochondrial damage and a causative factor in Parkinson's disease.

Mitochondria are the powerhouse of cells as they produce the bulk of ATP which is consumed by the cell. They form a highly interconnected network that is governed by fission and fusion processes. In addition, mitochondria and the endoplasmic reticulum (ER) are found in close proximity to each other and it is thought that they maintain contact sites to exchange molecules. The regulation and the function of these contact sites need to be further explored. The small GTPase Arf1 (ADP-ribosylation factor 1), which is best known for its essential role in the generation of coatomer protein I (COPI)-coated vesicles at the Golgi complex appears to be also essential for the dynamics and maintenance of mitochondrial function, presumably at ER–mitochondrial contact sites.

Astrocytes exhibit cellular excitability through variations in their intracellular calcium (Ca 2+ ) levels in response to synaptic activity. Astrocyte Ca 2+ elevations can trigger the release of neuroactive substances that can modulate synaptic transmission and plasticity, hence promoting bidirectional communication with neurons. Intracellular Ca 2+ dynamics can be regulated by several proteins located in the plasma membrane, within the cytosol and by intracellular organelles such as mitochondria. Spatial dynamics and strategic positioning of mitochondria are important for matching local energy provision and Ca 2+ buffering requirements to the demands of neuronal signalling. Although relatively unresolved in astrocytes, further understanding the role of mitochondria in astrocytes may reveal more about the complex bidirectional relationship between astrocytes and neurons in health and disease. In the present review, we discuss some recent insights regarding mitochondrial function, transport and turnover in astrocytes and highlight some important questions that remain to be answered.

Correct mitochondrial dynamics are essential to neuronal function. These dynamics include mitochondrial trafficking and quality-control systems that maintain a precisely distributed and healthy mitochondrial network, so that local energy demands or Ca 2+ -buffering requirements within the intricate architecture of the neuron can be met. Mitochondria make use of molecular machinery that couples these organelles to microtubule-based transport via kinesin and dynein motors, facilitating the required long-range movements. These motors in turn are associated with a variety of adaptor proteins allowing additional regulation of the complex dynamics demonstrated by these organelles. Over recent years, a number of new motor and adaptor proteins have been added to a growing list of components implicated in mitochondrial trafficking and distribution. Yet, there are major questions that remain to be addressed about the regulation of mitochondrial transport complexes. One of the core components of this machinery, the mitochondrial Rho GTPases Miro1 (mitochondrial Rho 1) and Miro2 have received special attention due to their Ca 2+ -sensing and GTPase abilities, marking Miro an exceptional candidate for co-ordinating mitochondrial dynamics and intracellular signalling pathways. In the present paper, we discuss the wealth of literature regarding Miro-mediated mitochondrial transport in neurons and recently highlighted involvement of Miro proteins in mitochondrial turnover, emerging as a key process affected in neurodegeneration.

Autophagy is a fundamental cellular process promoting survival under various environmental stress conditions. Selective types of autophagy have gained much interest recently as they are involved in specific quality control mechanisms removing, for example, aggregated proteins or dysfunctional mitochondria. This is considered to counteract the development of a number of neurodegenerative disorders and aging. Here we review the role of mitophagy and mitochondrial dynamics in ensuring quality control of mitochondria. In particular, we provide possible explanations why mitophagy in yeast, in contrast with the situation in mammals, was found to be independent of mitochondrial fission. We further discuss recent findings linking these processes to nutrient sensing pathways and the general stress response in yeast. In particular, we propose a model for how the stress response protein Whi2 and the Ras/PKA (protein kinase A) signalling pathway are possibly linked and thereby regulate mitophagy.

Mitochondria are involved in many fundamental processes underpinning plant growth, development and death. Owing to their multiple roles, as the sites of the tricarboxylic acid cycle and oxidative phosphorylation, as harbourers of their own genomes and as sensors of cell redox status, amongst others, mitochondria are in a unique position to act as sentinels of cell physiology. The plant chondriome is typically organized as a population of physically discrete organelles, but visualization of mitochondria in living tissues has shown that the mitochondrial population is highly interactive. Mitochondria are highly motile and movement on the cytoskeleton ensures that the physically discrete organelles come into contact with one another, which allows transient fusion, followed by division of the mitochondrial membranes. This article serves to review our current knowledge of mitochondrial fusion and division, and link this to recent discoveries regarding a putative mitochondrial ‘health-check’ and repair process, whereby non-repairable dysfunctional mitochondria can be removed from the chondriome. It is proposed that the unequal distribution of the multipartite plant mitochondrial genome between discrete organelles provides the driver for transient mitochondrial fusion that, in turn, is dependent on mitochondrial motility, and that both fusion and motility are necessary to maintain a healthy functional chondriome.