TMEM70 and TMEM242 help to assemble the rotor ring of human ATP synthase and interact with assembly factors for complex I

Abstract

Human mitochondrial ATP synthase is a molecular machine with a rotary action bound in the inner organellar membranes. Turning of the rotor, driven by a proton motive force, provides energy to make ATP from ADP and phosphate. Among the 29 component proteins of 18 kinds, ATP6 and ATP8 are mitochondrial gene products, and the rest are nuclear gene products that are imported into the organelle. The ATP synthase is assembled from them via intermediate modules representing the main structural elements of the enzyme. One such module is the c8-ring, which provides the membrane sector of the enzyme’s rotor, and its assembly is influenced by another transmembrane (TMEM) protein, TMEM70. We have shown that subunit c interacts with TMEM70 and another hitherto unidentified mitochondrial transmembrane protein, TMEM242. Deletion of TMEM242, similar to deletion of TMEM70, affects but does not completely eliminate the assembly of ATP synthase, and to a lesser degree the assembly of respiratory enzyme complexes I, III, and IV. Deletion of TMEM70 and TMEM242 together prevents assembly of ATP synthase and the impact on complex I is enhanced. Removal of TMEM242, but not of TMEM70, also affects the introduction of subunits ATP6, ATP8, j, and k into the enzyme. TMEM70 and TMEM242 interact with the mitochondrial complex I assembly (the MCIA) complex that supports assembly of the membrane arm of complex I. The interactions of TMEM70 and TMEM242 with MCIA could be part of either the assembly of ATP synthase and complex I or the regulation of their levels.

Defining the molecular mechanisms of the mitochondrial permeability transition through genetic manipulation of F-ATP synthase

“…2b ), which has also been observed in HAP1 cells after deletion of peripheral stalk subunits and of the c ring 26 – 28 . A possible explanation is that respiratory chain complex I and F-ATP synthase share the assembly factors TMEM70 and TMEM242, which could be part of a negative regulatory mechanism connecting the levels of complex I to those of F-ATP synthase 41 . Cell growth was also impaired in HeLa-Δg cells (Supplementary Fig.…”

Interplay between Mitochondrial Protein Import and Respiratory Complexes Assembly in Neuronal Health and Degeneration

“…The second transmembrane domain, instead, might be imported in a follow up step through a stop-transfer mechanism via the TIM23 complex as previously described for Cox2 in plants [ 256 ]. Interestingly, two assembly factors previously known for being involved in CI assembly, TMEM70 and TMEM242, were found acting as a scaffold for c-ring assembly [ 257 , 258 ].…”

TMEM135 is a Novel Regulator of Mitochondrial Dynamics and Physiology with Implications for Human Health Conditions

“…Given the known role of TMEM70, mutations in TMEM70 lead to oxidative phosphorylation (OXPHOS) deficiencies linked to many mitochondrial diseases that present as neonatal mitochondrial encephalo-cardiomyopathy in humans [ 14 , 15 , 17 , 18 , 19 ]. Likewise, TMEM242 affects the arrangement of ATP synthase [ 20 ], whereas deletion of both TMEM70 and TMEM242 prevents the assembly of ATP synthase, thereby affecting complex I [ 20 ].…”

“…In addition, TMEM is also involved in chemically induced hepatic steatosis (non-alcoholic fatty liver disease) [ 105 ] and hypertrophic cardiomyopathy [ 106 ]. Forced overexpression TMEM135 in mouse hearts led to a form of cardiomyopathy characterized by hypertrophy, increased collagen deposits, and premature cardiac aging [ 20 ].…”

“…Profiling of TMEM135 in patients to assess non-alcoholic fatty liver disease) [ 71 ], hypertrophic cardiomyopathy [ 72 ], and premature cardiac aging [ 20 ].…”