Mitochondrial biogenesis in exercise and in ageing

Abstract

Mitochondrial biogenesis is critical for the normal function of cells. It is well known that mitochondria are produced and eventually after normal functioning they are degraded. Thus, the actual level of mitochondria in cells is dependent both on the synthesis and the degradation. Ever since the proposal of the mitochondrial theory of ageing by Jaime Miquel in the 70's, it was appreciated that mitochondria, which are both a target and a source of radicals in cells, are most important organelles to understand ageing. Thus, a common feature between cell physiology of ageing and exercise is that in both situations mitochondria are critical for normal cell functioning.

Mitochondrial synthesis is stimulated by the PGC-1α–NRF1–TFAM pathway. PGC-1α is the first stimulator of mitochondrial biogenesis. NRF1 is an intermediate transcription factor which stimulates the synthesis of TFAM which is a final effector activating the duplication of mitochondrial DNA molecules. This pathway is impaired in ageing. On the contrary, exercise, particularly aerobic exercise, activates mitochondriogenesis in the young animal but its effects on mitochondrial biogenesis in the old animal are doubtful. In this chapter we consider the interrelationship between mitochondrial biogenesis stimulated by exercise and the possible impairment of this pathway in ageing leading to mitochondrial deficiency and eventually muscle sarcopenia.

Introduction

Mitochondria are one of the most intensely studied organelles in the cell. It has, of course, the classical function of producing energy through the respiratory chain. However, many more functions have emerged particularly related to the role of these organelles in cellular signalling. For instance, mitochondria generate signals which are essential for the onset of the “mitochondrial pathway of apoptosis”. This is unleashed by the release of cytochrome c under suitable conditions, which leads to activation of caspase-3 and eventually cell death [1]. Much more recently, experimental evidence has come from various laboratories that proteins which a few years ago were thought to be completely cytosolic, enter mitochondria and regulate their function. A very important one is the MAP kinase JNK which enters the mitochondria and regulates the critical enzyme pyruvate dehydrogenase by phosphorylation [2], [3]. Very recently, telomerase has also been shown to accumulate in mitochondria and in fact to serve as an antioxidant in this organelle [4]. Thus, the relevance of mitochondria in cell function continues to go and it is the subject of critical scrutiny.

Mitochondria are involved in two physiological situations of great importance, namely physical exercise and ageing [5]. The fact that physical training, in particular aerobic training, is a very clear-cut stimulus for mitochondriogenesis is beyond doubt. Animals or persons who train show an increased number of mitochondria with the subsequent increased capability of oxygen utilisation [5], [6], [7].

Mitochondria are also very relevant to ageing. In fact, the free radical theory of ageing first postulated by Harman in 1956 [8] together with the findings by Boveris and Sies in the laboratory of Britton Chance that 2% of oxygen consumed by mitochondria in state 4 is converted to hydrogen peroxide [9], led Denham Harman to postulate that mitochondria might be critical in the generation of radicals which are responsible for damage associated with ageing. This was further refined by Jaime Miquel who in the 70's formulated the mitochondrial free radical of ageing. Two critical contributions of Miquel were: underpinning the importance of mitochondrial DNA as a target of oxidants produced during ageing and pointing out that mitochondriogenesis might be impaired in ageing and that in fact a lower rate of the renewal of mitochondria was one of the critical events which led to damage associated with ageing [10]. The majority of the studies performed by Jaime Miquel in the United States in the 70's were basically histological [11]. Later on in the 90's, we reported that mitochondria are damaged inside cells [12], [13]. This was almost simultaneously confirmed by the group of Bruce Ames [14]. Moreover, we found that oxidative damage to mitochondrial DNA was increased in ageing and this could prevent it by antioxidant supplementations [15]. So the initial prediction of the free radical theory of ageing i.e., that mitochondrial DNA was a key target of damage associated with ageing could be experimentally proved. However, the prediction that ageing was associated with the lower renewal of mitochondria in cells took much longer. The major reason was that it was (and still is) difficult to assess the amount of mitochondria in a cell, particularly in a dynamic way, i.e. whether interventions accelerate or decrease the rate of mitochondriogenesis. To solve this problem, the elucidation of the mitochondriogenic pathway was required.