Leber's hereditary optic neuropathy is a maternally inherited disease resulting in optic nerve degeneration and cardiac dysrhythmia. A mitochondrial DNA replacement mutation was identified that correlated with this disease in multiple families. This mutation converted a highly conserved arginine to a histidine at codon 340 in the NADH dehydrogenase subunit 4 gene and eliminated an Sfa NI site, thus providing a simple diagnostic test. This finding demonstrated that a nucleotide change in a mitochondrial DNA energy production gene can result in a neurological disease.

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Mitochondria are chronically exposed to reactive oxygen intermediates. As a result, various tissues, including skeletal muscle and heart, are characterized by an age-associated increase in reactive oxidant-induced mitochondrial DNA (mtDNA) damage. It has been postulated that these alterations may result in a decline in the content and rate of production of ATP, which may affect tissue function, contribute to the aging process, and lead to several disease states. We show that with age, ATP content and production decreased by approximately 50% in isolated rat mitochondria from the gastrocnemius muscle; however, no decline was observed in heart mitochondria. The decline observed in skeletal muscle may be a factor in the process of sarcopenia, which increases in incidence with advancing age. Lifelong caloric restriction, which prolongs maximum life span in animals, did not attenuate the age-related decline in ATP content or rate of production in skeletal muscle and had no effect on the heart. 8-Oxo-7,8-dihydro-2'-deoxyguanosine in skeletal muscle mtDNA was unaffected by aging but decreased 30% with caloric restriction, suggesting that the mechanisms that decrease oxidative stress in these tissues with caloric restriction are independent from ATP availability. The generation of reactive oxygen species, as indicated by H2O2 production in isolated mitochondria, did not change significantly with age in skeletal muscle or in the heart. Caloric restriction tended to reduce the levels of H2O2 production in the muscle but not in the heart. These data are the first to show that an age-associated decline in ATP content and rate of ATP production is tissue specific, in that it occurs in skeletal muscle but not heart, and that mitochondrial ATP production was unaltered by caloric restriction in both tissues.

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Among the complex determinants of aging, mitochondrial dysfunction has been in the spotlight for a long time. As the hub for many cellular functions, the maintenance of an adequate pool of functional mitochondria is crucial for tissue homeostasis. Their unique role in energy supply makes these organelles essential, especially in those tissues strictly dependent on oxidative metabolism. Mitochondrial quality control (MQC) is ensured by pathways related to protein folding and degradation as well as by processes involving the entire organelle, such as biogenesis, dynamics, and mitophagy. Dysfunctional MQC, oxidative stress and inflammation are hallmarks of senescence and chronic degenerative diseases. One of the consequences of age-related failing MQC and oxidative stress is the release of mitochondria-derived damage-associated molecular patterns (DAMPs). Through their bacterial ancestry, these molecules contribute to mounting an inflammatory response by interacting with receptors similar to those involved in pathogen-associated responses. Mitochondrial DAMPs, especially cell-free mitochondrial DNA, have recently become the subject of intensive research because of their possible involvement in conditions associated with inflammation, such as aging and degenerative diseases. Here, we review the contribution of mitochondrial DAMPs to inflammation and discuss some of the mechanisms at the basis of their generation.