Mitochondria are the organelles producing most of the energy and play important roles in a variety of biochemical functions in
human cells. Mitochondrial defects can cause ATP deficiency and overproduction of reactive oxygen species, which are the major hallmarks
of mitochondrial diseases. Abundant evidence has suggested that mitochondrial dysfunction-elicited oxidative stress can play an
important role in the pathogenesis and progression of mitochondrial diseases. Mitochondria can respond to energy deficiency by the retrograde
signaling to trigger a number of molecular events to help the human cells to cope with physiological or environmental changes.
In this article, we first describe oxidative stress-induced cellular responses including metabolic adaptation, compensatory increase of mitochondrial
biogenesis, upregulation of antioxidant enzymes, and alteration of protein acetylation in human cells with mitochondrial dysfunction.
In this regard, we review recent findings to elucidate the mechanisms by which human cells motivate their mitochondria and the
antioxidant defense system to respond to energy deficiency and oxidative stress, which contribute to the adaptive metabolic reprogramming
in mitochondrial diseases. In addition, we emphasize the critical role of the activation of AMPK, Sirt1 and Sirt3 in the metabolic
adaptation of human cells harboring mitochondrial DNA mutations. Recent studies have revealed that AMPK and sirtuins-mediated signaling
pathways are involved in metabolic reprogramming, which is effected by upregulation of antioxidant defense system and mitochondrial
protein acetylation, in human cells with mitochondrial dysfunction. Finally, we discuss several potential modulators of bioenergetic
function such as coenzyme Q10, mitochondria-targeting antioxidants, resveratrol, and L-carnitine based on recent findings from
studies on human cells and animal models of mitochondrial diseases. Elucidation of the signaling pathway of this adaptive response to
oxidative stress triggered by mitochondrial dysfunction may enable us to gain a deeper insight into the communication between mitochondria
and the nucleus and guide us to develop novel therapeutic agents for effective treatment of mitochondrial diseases.