[Abstract unavailable

SummaryA decline in mitochondrial function plays a key role in the aging process and increases the incidence of age-related disorders. A deeper understanding of the intricate nature of mitochondrial dynamics, which is described as the balance between mitochondrial fusion and fission, has revealed that functional and structural alterations in mitochondrial morphology are important factors in several key pathologies associated with aging. Indeed, a recent wave of studies has demonstrated the pleiotropic role of fusion and fission proteins in numerous cellular processes, including mitochondrial metabolism, redox signaling, the maintenance of mitochondrial DNA and cell death. Additionally, mitochondrial fusion and fission, together with autophagy, have been proposed to form a quality-maintenance mechanism that facilitates the removal of damaged mitochondria from the cell, a process that is particularly important to forestall aging. Thus, dysfunctional regulation of mitochondrial dynamics might be one of the intrinsic causes of mitochondrial dysfunction, which contributes to oxidative stress and cell death during the aging process. In this Commentary, we discuss recent studies that have converged at a consensus regarding the involvement of mitochondrial dynamics in key cellular processes, and introduce a possible link between abnormal mitochondrial dynamics and aging. Journal of Cell Science (Chen and Chan, 2009). However, the relevance of mitochondrial fusion and fission to underlying mechanisms of aging has not been fully appreciated, in part because the molecular events that underlie the aging process have not yet been completely elucidated. In this Commentary, we discuss current knowledge of mitochondrial dynamics, structure and function in relation to key cellular events, including mitochondrial biogenesis, mtDNA homeostasis, autophagy and cell death. By providing a basic overview of mitochondrial fusion and fission events and their general function in these crucial biological processes during normal stable environmental conditions, we hope to portray how alterations in mitochondrial dynamics can contribute to the mitochondrial dysfunction that is commonly associated with aging. Mechanisms underlying mitochondrial dynamicsMitochondria are highly complex and dynamic organelles that can alter their organization, shape and size, depending on intracellular and extracellular signals (Bereiter-Hahn and Voth, 1994;Rube and van der Bliek, 2004). Mitochondria undergo a continuous cycle of fusion and fission, and the balance between these opposing events determines the morphology of the organelle (Chen and Chan, 2004) (Fig. 2). Whereas decreased fusion can result in mitochondrial fragmentation because of excessive fission, decreased fission can generate long and highly interconnected mitochondria (Sesaki and Jensen, 1999).During the past decade, various cellular components have been identified as key mediators of mitochondrial fusion and fission in yeast (Hoppins et al., 2007;Merz et al., 2007;Okamoto and Shaw, 2005). The...

Summary Age-related loss of muscle mass and strength (sarcopenia) leads to a decline in physical function and frailty in the elderly. Among the many proposed underlying causes of sarcopenia, mitochondrial dysfunction is inherent in a variety of aged tissues. The intent of this study was to examine the effect of aging on key groups of regulatory proteins involved in mitochondrial biogenesis and how this relates to physical performance in two groups of sedentary elderly participants, classified as high- and low-functioning based on the Short Physical Performance Battery test. Muscle mass was decreased by 38% and 30% in low-functioning elderly (LFE) participants when compared to young and high-functioning elderly (HFE) participants, respectively, and positively correlated to physical performance. Mitochondrial respiration in permeabilized muscle fibers was reduced (41%) in the LFE group when compared to the young, and this was associated with a 30% decline in COX activity. Levels of key metabolic regulators, SIRT3 and PGC-1α were significantly reduced (50%) in both groups of elderly participants when compared to young. Similarly, the fusion protein OPA1 was lower in muscle from elderly subjects, however no changes were detected in Mfn2, Drp1 or Fis1 among the groups. In contrast, protein import machinery (PIM) components Tom22 and cHsp70 were increased in the LFE group when compared to the young. This study suggests that aging in skeletal muscle is associated with impaired mitochondrial function and altered biogenesis pathways, and that this may contribute to muscle atrophy and the decline in muscle performance observed in the elderly population.

The transcriptional coactivator the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) has been identified as an important mediator of mitochondrial biogenesis based on its ability to interact with transcription factors that activate nuclear genes encoding mitochondrial proteins. The induction of PGC-1alpha protein expression under conditions that provoke mitochondrial biogenesis, such as contractile activity or thyroid hormone (T(3)) treatment, is not fully characterized. Thus we related PGC-1alpha protein expression to cytochrome c oxidase (COX) activity in 1) tissues of varying oxidative capacities, 2) tissues from animals treated with T(3), and 3) skeletal muscle subject to contractile activity both in cell culture and in vivo. Our results demonstrate a strong positive correlation (r = 0.74; P < 0.05) between changes in PGC-1alpha and COX activity, used as an index of mitochondrial adaptations. The highest constitutive levels of PGC-1alpha were found in the heart, whereas the lowest were measured in fast-twitch white muscle and liver. T(3) increased PGC-1alpha content similarly in both fast- and slow-twitch muscle, as well as in the liver, but not in heart. T(3) also induced early (6 h) increases in AMP-activated protein kinase (AMPKalpha) activity, as well as later (5 day) increases in p38 MAP kinase activity in slow-twitch, but not in fast-twitch, muscle. Contractile activity provoked early increases in PGC-1alpha, coincident with increases in mitochondrial transcription factor A (Tfam), and nuclear respiratory factor-1 (NRF-1) protein expression, suggesting that PGC-1alpha is physiologically important in coordinating the expression of the nuclear and mitochondrial genomes. Ca(2+) ionophore treatment of muscle cells led to an approximately threefold increase in PGC-1alpha protein, and contractile activity induced rapid and marked increases in both p38 MAP kinase and AMPKalpha activities. 5-Aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) treatment of muscle cells also led to parallel increases in AMPKalpha activity and PGC-1alpha protein levels. These data are consistent with observations that indicate that increases in PGC-1alpha protein are affected by Ca(2+) signaling mechanisms, AMPKalpha activity, as well as posttranslational phosphorylation events that increase PGC-1alpha protein stability. Our data support a role for PGC-1alpha in the physiological regulation of mitochondrial content in a variety of tissues and suggest that increases in PGC-1alpha expression form part of a unifying pathway that promotes both T(3)- and contractile activity-induced mitochondrial adaptations.

SUMMARY Skeletal muscle is a highly malleable tissue, capable of pronounced metabolic and morphological adaptations in response to contractile activity(i.e. exercise). Each bout of contractile activity results in a coordinated alteration in the expression of a variety of nuclear DNA and mitochondrial DNA(mtDNA) gene products, leading to phenotypic adaptations. This results in an increase in muscle mitochondrial volume and changes in organelle composition,referred to as mitochondrial biogenesis. The functional consequence of this biogenesis is an improved resistance to fatigue. Signals initiated by the exercise bout involve changes in intracellular Ca2+ as well as alterations in energy status (i.e. ATP/ADP ratio) and the consequent activation of downstream kinases such as AMP kinase and Ca2+-calmodulin-activated kinases. These kinases activate transcription factors that bind DNA to affect the transcription of genes, the most evident manifestation of which occurs during the post-exercise recovery period when energy metabolism is directed toward anabolism, rather than contractile activity. An important protein that is affected by exercise is the transcriptional coactivator PGC-1α, which cooperates with multiple transcription factors to induce the expression of nuclear genes encoding mitochondrial proteins. Once translated in the cytosol, these mitochondrially destined proteins are imported into the mitochondrial outer membrane, inner membrane or matrix space via specific import machinery transport components. Contractile activity affects the expression of the import machinery, as well as the kinetics of import, thus facilitating the entry of newly synthesized proteins into the expanding organelle. An important set of proteins that are imported are the mtDNA transcription factors, which influence the expression and replication of mtDNA. While mtDNA contributes only 13 proteins to the synthesis of the organelle, these proteins are vital for the proper assembly of multi-subunit complexes of the respiratory chain,when combined with nuclear-encoded protein subunits. The expansion of skeletal muscle mitochondria during organelle biogenesis involves the assembly of an interconnected network system (i.e. a mitochondrial reticulum). This expansion of membrane size is influenced by the balance between mitochondrial fusion and fission. Thus, mitochondrial biogenesis is an adaptive process that requires the coordination of multiple cellular events, including the transcription of two genomes, the synthesis of lipids and proteins and the stoichiometric assembly of multisubunit protein complexes into a functional respiratory chain. Impairments at any step can lead to defective electron transport, a subsequent failure of ATP production and an inability to maintain energy homeostasis.

Muscle loss during aging and disuse is a highly prevalent and disabling condition, but knowledge about cellular pathways mediating muscle atrophy is still limited. Given the postmitotic nature of skeletal myocytes, the maintenance of cellular homeostasis relies on the efficiency of cellular quality control mechanisms. In this scenario, alterations in mitochondrial function are considered a major factor underlying sarcopenia and muscle atrophy. Damaged mitochondria are not only less bioenergetically efficient, but also generate increased amounts of reactive oxygen species, interfere with cellular quality control mechanisms, and display a greater propensity to trigger apoptosis. Thus, mitochondria stand at the crossroad of signaling pathways that regulate skeletal myocyte function and viability. Studies on these pathways have sometimes provided unexpected and counterintuitive results, which suggests that they are organized into a complex, heterarchical network that is currently insufficiently understood. Untangling the complexity of such a network will likely provide clinicians with novel and highly effective therapeutics to counter the muscle loss associated with aging and disuse. In this review, we summarize the current knowledge on the mechanisms whereby mitochondrial dysfunction intervenes in the pathogenesis of sarcopenia and disuse atrophy, and highlight the prospect of targeting specific processes to treat these conditions.

Chronic muscle use increases the ratio of fusion:fission proteins, leading to reticular mitochondria, whereas muscle disuse and aging result in a decrease in this ratio, culminating in fragmented organelles.

Behavioural and hereditary conditions are known to decrease mitochondrial volume and function within skeletal muscle. This reduces endurance performance, and is manifest both at high- and low-intensity levels of exertion. A programme of regular endurance exercise, undertaken over a number of weeks, produces significant adaptations within skeletal muscle such that noticeable improvements in oxidative capacity are evident, and the related decline in endurance performance can be attenuated. Notwithstanding the important implications that this has for the highly trained endurance athlete, an improvement in mitochondrial volume and function through regular physical activity also endows the previously sedentary and/or aging population with an improved quality of life, and a greater functional independence. An understanding of the molecular and cellular mechanisms that govern the increases in mitochondrial volume with repeated bouts of exercise can provide insights into possible therapeutic interventions to care for those with mitochondrially-based diseases, and those unable to withstand regular physical activity. This review focuses on the recent developments in the molecular aspects of mitochondrial biogenesis in chronically exercising muscle. Specifically, we discuss the initial signalling events triggered by muscle contraction, the activation of transcription factors involved in both nuclear and mitochondrial DNA transcription, as well as the post-translational import mechanisms required for mitochondrial biogenesis. We consider the importance and relevance of chronic physical activity in the induction of mitochondrial biogenesis, with particular emphasis on how an endurance training programme could positively affect the age-related decline in mitochondrial content and delay the progression of age- and physical inactivity-related diseases.