SUMMARY Although mature myocytes rely on mitochondria as the primary source of energy, the role of mitochondria in the developing heart is not well known. Here, we find closure of the mitochondrial permeability transition pore (mPTP) drives maturation of mitochondrial structure and function and myocyte differentiation. Cardiomyocytes at embryonic day (E) 9.5, when compared to E13.5, displayed fragmented mitochondria with few cristae, a less polarized mitochondrial membrane potential, higher reactive oxygen species (ROS) levels, and an open mPTP. Pharmacologic and genetic closing of the mPTP yielded maturation of mitochondrial structure and function, lowered ROS, and increased myocyte differentiation (measured by counting Z-bands). Furthermore, myocyte differentiation was inhibited and enhanced with oxidant and antioxidant treatment, respectively, suggesting that redox signaling pathways lie downstream of mitochondria to regulate cardiac myocyte differentiation.

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Peroxisome proliferator-activated receptor ␥ (PPAR␥) has been proposed as a therapeutic target for neurodegenerative diseases because of its anti-inflammatory action in glial cells. However, PPAR␥ agonists prevent ␤-amyloid (A␤)-induced neurodegeneration in hippocampal neurons, and PPAR␥ is activated by the nerve growth factor (NGF) survival pathway, suggesting a neuroprotective anti-inflammatory independent action. Here we show that the PPAR␥ agonist rosiglitazone (RGZ) protects hippocampal and dorsal root ganglion neurons against A␤-induced mitochondrial damage and NGF deprivation-induced apoptosis, respectively, and promotes PC12 cell survival. In neurons and in PC12 cells RGZ protective effects are associated with increased expression of the Bcl-2 anti-apoptotic protein. NGF-differentiated PC12 neuronal cells constitutively overexpressing PPAR␥ are resistant to A␤-induced apoptosis and morphological changes and show functionally intact mitochondria and no increase in reactive oxygen species when challenged with up to 50 M H 2 O 2 . Conversely, cells expressing a dominant negative mutant of PPAR␥ show increased A␤-induced apoptosis and disruption of neuronal-like morphology and are highly sensitive to oxidative stress-induced impairment of mitochondrial function. Cells overexpressing PPAR␥ present a 4-to 5-fold increase in Bcl-2 protein content, whereas in dominant negative PPAR␥-expressing cells, Bcl-2 is barely detected. Bcl-2 knockdown by small interfering RNA in cells overexpressing PPAR␥ results in increased sensitivity to A␤ and oxidative stress, further suggesting that Bcl-2 up-regulation mediates PPAR␥ protective effects. PPAR␥ prosurvival action is independent of the signal-regulated MAPK or the Akt prosurvival pathways. Altogether, these data suggest that PPAR␥ supports survival in neurons in part through a mechanism involving increased expression of Bcl-2.

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In Alzheimer disease (AD) mitochondrial abnormalities occur early in the pathogenic process and likely play a significant role in disease progression. Tau is a microtubule-associated protein that is abnormally processed in AD, and a connection between tau pathology and mitochondrial impairment has been proposed. However, few studies have examined the relationship between pathological forms of tau and mitochondrial dysfunction. We recently demonstrated that inducible expression of tau truncated at Asp-421 to mimic caspase cleavage (T4C3) was toxic to immortalized cortical neurons compared with a fulllength tau isoform (T4). In this study we investigated the effects of T4C3 on mitochondrial function. Expression of T4C3 induced mitochondrial fragmentation and elevated oxidative stress levels in comparison with T4-expressing cells. Thapsigargin treatment of T4 or T4C3 cells, which causes an increase in intracellular calcium levels, resulted in a significant decrease in mitochondrial potential and loss of mitochondrial membrane integrity in T4C3 cells when compared with cells expressing T4. The mitochondrial fragmentation and mitochondrial membrane damage were ameliorated in T4C3 cells by pretreatment with cyclosporine A or FK506, implicating the calcium-dependent phosphatase calcineurin in these pathogenic events. Increased calcineurin activity has been reported in AD brain, and thus, inhibition of this phosphatase may provide a therapeutic target for the treatment of AD.Tau is a microtubule-associated protein which in a hyperphosphorylated state forms paired helical filaments; the major component of neurofibrillary tangles (NFTs) 3 (1, 2). These NFTs are one of the primary pathophysiological hallmarks of Alzheimer disease (AD) and were originally suggested to play a major role in facilitating neuronal degeneration (1). However, recent studies now suggest that mature tangles may not be the toxic species (3, 4). For example, in a repressible tau overexpression transgenic mouse model, turning off tau expression attenuated memory impairment and neuronal loss, whereas NFTs continued to accumulate (5). Furthermore, reduction of endogenous wild type tau attenuated behavioral abnormalities in an APP transgenic AD mouse model, in which substantial NFT pathology is absent (6). These and other findings suggest that a form or forms of tau that precede NFT formation may be the toxic species. There is increasing evidence that, in addition to aberrant phosphorylation, caspase cleavage of tau plays a role in the oligomerization and formation of a pathological tau species in AD (7,8). Tau is an in vitro substrate for caspase-3 and is readily cleaved at Asp-421, the caspase-3 cleavage site, located on the carboxyl-terminal end of the protein (7-10). This cleavage event results in a highly fibrillogenic tau isoform which in in vitro studies aggregates more readily and to a greater extent than full-length tau and facilitates aggregate formation of fulllength tau (7,8). Antibodies that specifically recognize Asp-421-truncated tau show ...