**1. Introduction**

Cells are highly organized units with multifaceted functional and structural interactions between various subcellular systems. A large number of studies provides strong evidence that elucidating individual organelles alone is not sufficient, and only systemic approaches must be applied for understanding intracellular signaling pathways and crosstalk between subcellular organelles. This may involve a "systems biology" approach and combinations of several most modern technologies such as genetic manipulations, live cell imaging, mathematical modelling, etc. In high oxygen consuming organs like the heart, energy supply (ATP) is provided by mitochondria in the reactions of oxidative phosphorylation (OXPHOS). Notably, mitochondria actively interact with other subcellular organelles and systems like cytoskeleton and sarcoplasmic reticulum (SR) [1–12]. Many cytoskeletal elements play a vital role in the structural and functional organization of mitochondria, including mitochondrial shape and morphology, dynamics, motility, and mitosis [13–17]. Most importantly, the interaction of mitochondria with some cytoskeletal proteins and their connections to voltage dependent anion channel (VDAC) can be involved in the coordination of mitochondrial function [18–23] (Figure 1). In the heart, mitochondrial bioenergetics and oxygen consumption are linearly dependent on the cardiac contractile activity [24,25] at rather stable concentration of the main mitochondrial regulator adenosine diphosphate (ADP), which is a central element in mitochondrial physiology. The exact mechanisms of how mitochondria precisely respond to the heart energy demand remained unknown for a long time and require further investigations. A growing body of evidence shows that the cells contain intracellular metabolic micro-compartments provided by multidirectional mitochondrial interactions with other subcellular organelles and macromolecules, in particular, specific cytoskeletal proteins [26–34]. In this review, we summarize and discuss previous studies that provide strong evidence for the role of cytoskeletal proteins, in particular, tubulin beta-II and plectin 1b, in the regulation of mitochondrial bioenergetics and energy fluxes via the energy-transferring supercomplex VDAC-mitochondrial creatine kinase (MitCK)-ATP-ADP translocase (ANT) under physiological and pathological conditions.

**Figure 1.** The central roles of cytoskeleton and its interactions in mitochondrial and entire cell physiology.
