Mitochondrial biogenesis is the process by which cells increase mitochondrial numbers. It was first described by John Holloszy in the 1960s, when it was discovered that physical endurance training induced higher mitochondrial content levels, leading to greater glucose uptake by muscles. Mitochondrial biogenesis is activated by numerous different signals during times of cellular stress or in response to environmental stimuli, such as aerobic exercise. Background The ability for a mitochondrion to self-replicate is rooted in its evolutionary history. It is commonly thought that mitochondria descend from cells that formed endosymbiotic relationships with α-protobacteria; they have their own genome for replication. However, recent evidence suggests that mitochondria may have evolved without symbiosis. The mitochondrion is a key regulator of the metabolic activity of the cell, and is also an important organelle in both production and degradation of free radicals. It is postulated that higher mitochondrial copy number (or higher mitochondrial mass) is protective for the cell. Mitochondria are produced from the transcription and translation of genes both in the nuclear genome and in the mitochondrial genome. The majority of mitochondrial protein comes from the nuclear genome, while the mitochondrial genome encodes parts of the electron transport chain along with mitochondrial rRNA and tRNA. Mitochondrial biogenesis increases metabolic enzymes for glycolysis, oxidative phosphorylation and ultimately a greater mitochondrial metabolic capacity. However, depending on the energy substrates available and the redox state of the cell, the cell may increase or decrease the number and size of mitochondria. Critically, mitochondrial numbers and morphology vary according to cell type and context-specific demand, whereby the balance between mitochondrial fusion/fission regulates mitochondrial distribution, morphology, and function. Protein import Since the majority of mitochondrial protein comes from the nuclear genome, the proteins need to be properly targeted and transported into the mitochondria to perform their functions. First, mRNA is translated in the cell’s cytosol. The resulting unfolded precursor proteins will then be able to reach their respective mitochondrial compartments. Precursor proteins will be transported to one of four areas of the mitochondria, which include the outer membrane, inner membrane, intermembrane space, and matrix. All proteins will enter the mitochondria by a translocase on the outer mitochondrial membrane (TOM). Some proteins will have an N-terminal targeting signal, and these proteins will be detected and transported into the matrix, where they will then be cleaved and folded. Other proteins may have targeting information in their sequences and will not include