Over the past decades, significant progression has been made in understanding the cellular processes involved in heart failure, which has positively contributed to drug development in this field. However, in spite of new therapies able to improve patient's quality of life and survival 
, heart failure remains the main cause of death worldwide. Thus, there is a compelling need for new pharmacological and non-pharmacological therapies that could improve clinical outcomes. To fulfil this issue, a number of studies have focused on identifying intracellular distal strategic nodes where signals converge and/or serve as multi-effector brakes to suppress or reverse heart failure, which would become attractive targets for heart failure therapy.
Due to its pivotal role in bioenergetics, calcium homeostasis, redox regulation and cell death, mitochondria have been considered an intracellular organelle capable of orchestrating biochemical processes across the cell 
. Indeed, much of the current research focuses on understanding the crosstalk between mitochondrial and the rest of the cell. In the present study, we found that mitochondrial dysfunction-associated 4-HNE accumulation, a highly reactive α,β-unsaturated aldehyde and a major secondary product of lipid peroxidation, contributes to protein quality control disruption by directly targeting the proteasome in failing hearts. Moreover, we demonstrated that in vitro
4-HNE-modification/inactivation of proteasome occurs in an irreversible manner, while reduction of free sulphydryl groups prior to 4-HNE incubation abolished the inhibition of proteasomal chymotrypsin-like activity. Our study has shown for the first time that modification/inactivation of the cardiac proteasome by the lipid peroxidation product 4-HNE occurs in heart failure. Others have observed the same phenomenon during acute coronary occlusion/reperfusion, cerebral ischemia and aging 
The proteasome has been implicated in the removal of polyubiquitinated and oxidatively modified proteins 
. Therefore, impairment of proteasomal proteolytic activity by 4-HNE may negatively affect cellular protein quality control and further contributes to cell death. In agreement with these findings, we observed a striking inactivation of proteasomal chymotrypsin-like activity paralleled by accumulation of oxidatively modified, misfolded and polyubiquitinated proteins in failing hearts. These responses were accompanied by increased expression of small chaperones. Over-expression of small chaperones such as HSP25 and αβ crystallin is related to cellular protection against misfolded protein accumulation 
and cell death 
under acute insults (i.e. acute cardiac ischemia-reperfusion injury). However, during chronic degenerative diseases such as heart failure, increased chaperones expression does not overcome the deleterious effects generated by accumulation of misfolded proteins.
Considering that maintenance of protein quality control is crucial to protect long-lived cells, such as cardiomyocytes and neurons, we evaluated whether mitochondrial dysfunction-mediated oxidative stress could affect proteasomal activity and overall protein quality control in cultured isolated cardiomyocytes. Either Antimycin A or H2
resulted in proteasomal inactivation, accumulation of oxidatively modified proteins and cell death in cultured cardiomyocytes. These findings demonstrate that oxidative stress-mediated chymotrypsin-like proteasomal inhibition (the main proteasomal proteolytic site involved in protein degradation and the most sensitive to 4-HNE modification) 
decreases cardiomyocyte viability and contributes, at least in part, to the disruption of cardiac protein quality control in cardiomyocytes. We have previously shown that improvement of proteasomal activity using pharmacological tools protects neonatal cardiomyocytes against H2
-induced cell death 
Emerging studies have revealed that disruption of cardiac mitochondrial metabolism and/or proteasomal insufficiency are not only implicated but also play an important role in cardiac pathogenesis. In fact, selective pharmacological and genetic therapies capable to rescue either mitochondrial metabolism or proteasomal activity improve cardiac function in different heart disease animal models 
. However, considering that both mitochondrial metabolism and proteasomal function are highly regulated by different cellular processes, we cannot exclude the possibility that these changes are secondary to the compromised cardiac function. Therefore, further studies investigating both direct and indirect proteasomal regulation by oxidative stress during heart failure progression are required. Also, the contribution of oxidative stress to other proteolytic systems such as autophagic/lysosomal pathways, and its effect on cardiac protein quality control in HF should be considered.
The possible mechanisms involved in 4-HNE-mediated proteasomal inhibition have been previously described in different cell lines and systems, including the heart. Analysis of two-dimension gel electrophoresis from purified proteasomes followed by mass spectrometry demonstrated that 4-HNE modification is not a random process and that specific proteasomal subunits, mainly α-subunits, are targeted by 4-HNE in the heart 
. However, since the proteasomal catalytic sites are located in the β subunits (β1, β2 and β5), it has been suggested that an indirect mechanism, probably mediated by protein-protein interactions between regulatory and catalytic subunits, drives the inhibition of proteasomal peptidase activity mediated by 4-HNE. Indeed, further studies are required to better clarify this issue.
Another important finding of this study is the efficacy of exercise training in restoring cardiac mitochondrial function, proteasomal activity and protein quality control in heart failure animals. Exercise capacity has been widely recognized an independent predictor of mortality in patients with cardiovascular diseases 
. Moreover, exercise training is considered an important adjuvant in the treatment of heart failure since it increases both peak VO2
and exercise tolerance, resulting in improved patient outcome and quality of life 
. However, the mechanisms underlying exercise-induced beneficial effect on heart failure are not completely understood.
Over the last decades, several studies have demonstrated the contribution of exercise training to improve expression of mitochondrial markers of biogenesis and metabolism in heart failure. However, the contribution of exercise training to mitochondrial physiology and its extension to cytosolic systems related to cell survival during heart failure remains unclear. A recent study has demonstrated that low-intensity interval exercise training decreases calcium-induced mitochondrial permeability transition in aortic-banded miniature swine 
, which may positively affect cytosolic systems. In addition, exercise training has been shown to improve cardiac redox balance in young and old healthy animals 
. We extended these findings by showing that 8 weeks of aerobic exercise training restored oxidative phosphorylation efficiency along with a reduction in H2
release and increased maximum calcium uptake in isolated mitochondria from myocardial infarction-induced heart failure rats. Interestingly, exercise training had a positive impact on cytosolic protein quality control machinery by re-establishing the proteasomal activity in failing hearts. These findings suggest that reduced cardiac oxidative stress along with better protein quality control are associated with the benefits promoted by exercise training in heart failure rats. However, considering the complexity of mitochondrial metabolism and protein quality control machinery, further investigations need to be conducted in order to establish a cause-and-effect relationship as well as clarify other possible regulatory mechanisms regulated by exercise training in heart failure.
In summary, we provide evidence that myocardial-infarction induced heart failure rats display a prominent cardiac mitochondrial dysfunction, 4-HNE accumulation and cytosolic protein quality control disruption. In addition, the ability of exercise training to rescue mitochondrial function, decrease 4-HNE accumulation and improve cardiac protein quality control in heart failure highlights an important molecular mechanism underlying the benefits of exercise training in failing hearts.