Journal of internal medicine
-
Mutations in the mitochondrial genome are the cause of many debilitating neuromuscular disorders. Currently, there is no cure or treatment for these diseases, and symptom management is the only relief doctors can provide. Although supplements and vitamins are commonly used in treatment, they provide little benefit to the patient and are only palliative. ⋯ This is a useful feature to take advantage of for gene therapy applications, as not every mutant copy of mtDNA needs to be eliminated, but only enough to shift the heteroplasmic ratio below the disease threshold. Several DNA-editing enzymes have been used to shift heteroplasmy in cell culture and mice. This review provides an overview of these enzymes and discusses roadblocks of applying these to gene therapy in humans.
-
Mitochondria play central roles in cellular energetics, metabolism and signalling. Efficient respiration, mitochondrial quality control, apoptosis and inheritance of mitochondrial DNA depend on the proper architecture of the mitochondrial membranes and a dynamic remodelling of inner membrane cristae. Defects in mitochondrial architecture can result in severe human diseases affecting predominantly the nervous system and the heart. ⋯ These protein complexes and phospholipids are embedded in a network of functional interactions. They communicate with each other and additional factors, enabling them to balance different aspects of cristae biogenesis and to dynamically remodel the inner mitochondrial membrane. Genetic alterations disturbing these membrane-shaping factors can lead to human pathologies including fatal encephalopathy, dominant optic atrophy, Leigh syndrome, Parkinson's disease and Barth syndrome.
-
Mitochondrial medicine is a field that expanded exponentially in the last 30 years. Individually rare, mitochondrial diseases as a whole are probably the most frequent genetic disorder in adults. The complexity of their genotype-phenotype correlation, in terms of penetrance and clinical expressivity, natural history and diagnostic algorithm derives from the dual genetic determination. ⋯ Yet, from the initial restriction to the narrow field of oxidative phosphorylation dysfunction, the landscape of mitochondrial functions impinging on cellular homeostasis, driving life and death, is impressively enlarged. Finally, from the clinical standpoint, starting from the neuromuscular field, where brain and skeletal muscle were the primary targets of mitochondrial dysfunction as energy-dependent tissues, after three decades virtually any subspecialty of medicine is now involved. We will summarize the key clinical pictures and pathogenic mechanisms of mitochondrial diseases in adults.
-
Cardiovascular disease (CVD) is the most common cause of death in industrialized countries. One underlying cause is atherosclerosis, which is a systemic disease characterized by plaques of retained lipids, inflammatory cells, apoptotic cells, calcium and extracellular matrix (ECM) proteins in the arterial wall. ⋯ Here, the ECM and tissue repair play an important role in plaque stability, vulnerability and progression. This review will focus on ECM remodelling in atherosclerotic plaques, with focus on how ECM biomarkers might predict plaque vulnerability and outcome.
-
The current review uses rheumatoid arthritis (RA) as a prominent example for how studies on the interplay between environmental and genetic factors in defined subsets of a disease can be used to formulate aetiological hypotheses that subsequently can be tested for causality using molecular and functional studies. Major discussed findings are that exposures to airways from many different noxious agents including cigarette smoke, silica dust and more interact with major susceptibility genes, mainly HLA-DR genetic variants in triggering antigen-specific immune reactions specific for RA. ⋯ The findings referred to in the review have led to a change of paradigms for very early therapy and prevention of RA and to efforts towards what we have named 'personalized prevention'. We believe that the progress described here for RA will be of relevance for research and practice also in other immune-mediated diseases.